Historical Background and Epidemiology of Acute Venous Thromboembolic Disease

The incidence of deep venous thrombosis (DVT) ranges from 5 to 9 per 10,000 person-years in the general population, and the incidence of venous thromboembolism (DVT and pulmonary embolism [PE] combined) (VTE) is about 14 per 10,000 person-years.^1,2 This equates to more than 275,000 new cases of VTE per year in the United States.³ The number of identifiable risk factors that predispose to the development of VTE has steadily grown. This information has allowed physicians to provide more effective thromboembolism prophylaxis that is evidence-based and stratified according to the number of risk factors present. In patients with established DVT and PE, there has been a relatively recent emphasis evaluating the rate of recurrence and the clinical factors that predispose to recurrent VTE. In turn, the type and duration of long-term anticoagulation also continue to be stratified, based on the number of risk factors for recurrence.

Physicians from a variety of medical and surgical specialties participate in the care of these patients, and vascular surgeons often are called on to assist in their care and should therefore be familiar with the risk factors for VTE and the optimal medical therapy for these patients. This chapter describes risk factors for a first episode of VTE and the options for initial anticoagulation. An increasing number of risk factors and associated conditions that increase the predilection for recurrent VTE continue to be identified. The optimal duration and type of longer-term antithrombotic therapy are also covered, and the role of adjunctive vena cava filters is discussed briefly. VTE prophylaxis, modalities for the diagnosis of VTE, and thrombolytic therapy for VTE are beyond the scope of this chapter and are not discussed in detail.

Etiology and Natural History of Acute Venous Thromboembolism

APC, Activated protein C; HRT, hormone replacement therapy; OCP, oral contraceptives; VTE, venous thromboembolism.

When multiple inherited and acquired risk factors are present in the same patient, a synergistic effect may occur. Clinically manifest thrombosis most often occurs with the convergence of multiple genetic and acquired risk factors.⁴ Hospitalized patients have an average of 1.5 risk factors per patient, with 26% having three or more risk factors.⁵ Multiple risk factors often act synergistically to increase risk dramatically above the sum of individual risk factors. For example, patients who are heterozygous for factor V Leiden are at only moderately increased risk for VTE (4- to 8-fold). However, when combined with the additional risk of oral contraceptive use, the risk for VTE increases to approximately 35-fold, the same order of magnitude as for someone who is homozygous for factor V Leiden. The concomitant presence of obesity, advancing age, and factor V Leiden increases the thrombosis risk associated with hormone replacement therapy alone. In symptomatic outpatients, the odds ratio for an objectively documented DVT increases from 1.26 for one risk factor to 3.88 for three or more risk factors.⁶

Other factors associated with venous thrombosis include traditional cardiovascular risk factors (obesity, hypertension, diabetes), and there is a racial predilection among whites and African Americans compared with Asians and Native Americans. Certain gene variants (single nucleotide polymorphisms) are associated with a mild increased risk for DVT, and their presence may interact with other risk factors to increase the overall risk for venous thrombosis. However, testing for these polymorphisms is not common in clinical practice.

Natural History

Overt venous injury appears to be neither a necessary nor sufficient condition for thrombosis, although the role of biologic injury to the endothelium is increasingly apparent. Under conditions favoring thrombosis, the normally antithrombogenic endothelium may become prothrombotic, producing tissue factor, von Willebrand factor, and fibronectin. Stasis alone is probably also an inadequate stimulus in the absence of low levels of activated coagulation factors.⁷

The rate of VTE recurrence in patients with untreated isolated calf DVT is approximately 20% to 30%. In contrast, the rate of recurrence in patients with untreated proximal DVT is more difficult to determine, since the majority of patients with proximal DVT receive therapeutic anti-coagulation. Limited older data suggest that about 50% of patients with inadequately treated proximal DVT will develop symptomatic PE.

Therapeutic anticoagulation effectively stabilizes venous thrombus, prevents propagation, and promotes dissolution by endogenous plasmin and its mediators. However, there is a low rate of VTE recurrence, even with adequate dosages of heparin, low-molecular-weight heparin, pentasaccharides, and/or vitamin K antagonists. Most VTE recurrence takes place in the first few weeks after anticoagulant therapy is initiated, and it is dependent upon the location of the original DVT. Extension of isolated calf DVT is effectively attenuated by anticoagulation. However, even adequately treated proximal DVTs have a low rate of recurrence.

Diagnosis and Imaging

The patient presentation varies widely, depending on the extent of the venous thrombosis and the presence of concurrent medical and surgical problems. In some, the DVT will be discovered during routine screening of patients who are at high risk for VTE.

Imaging

The venous duplex scan is the most commonly performed test for the detection of infrainguinal DVT, both above and below the knee, with sensitivity and specificity of greater than 95% in symptomatic patients. In a venous duplex examination performed with the patient supine, spontaneous flow, variation of flow with respiration, and response of flow to the Valsalva maneuver, all are assessed. Continued improvements in ultrasound technology also have improved the ability to visualize color flow within the tibial veins. However, the primary method of detecting DVT with ultrasound is demonstration of the lack of compressibility of the vein with probe pressure on B-mode imaging. Normally, in transverse section, the vein walls should coapt with pressure (Figs. 12-1 and 12-2). Lack of coaptation indicates thrombus.

Fig 12–1 Common femoral vein without and with compression. Complete vein wall coaptation indicates absence of deep vein thrombosis.

Fig 12–2 Normal saphenofemoral junction.

Venography is the most definitive test for the diagnosis of DVT in both symptomatic and asymptomatic patients. Diagnostic venography involves placement of a small catheter in the dorsum of the foot, with injection of radiopaque contrast to produce projections in at least two views. Venography is not used routinely for the evaluation of lower extremity DVT because of associated complications. More commonly, it is used for imaging prior to operative venous reconstruction or catheter-based endovenous therapy.

Initial Antithrombotic Therapy for Acute Venous Thromboembolism

Once the diagnosis of VTE has been made, antithrombotic therapy should be initiated promptly. The following dosing protocols are the more commonly used treatment regimens, but they are not applicable to all patient populations. In patients who require anticoagulation for acute VTE disease, initial anticoagulation usually is administered parenterally with one of the medications listed in Table 12-2. Initial anticoagulation should be continued for at least 5 days, and most patients may begin warfarin therapy on the same day they begin parenteral anticoagulation. Parenteral anticoagulation may be discontinued once the prothrombin time–to–international normalized ratio (PT/INR) is in the therapeutic range (INR goal 2.5, range 2.0 to 3.0) for longer than 24 hours (i.e., two consecutive daily INR values of 2.0 to 3.0).

 TABLE 12–2 Approved Parenteral Medications for Initiation of Anticoagulation

IV, Intravenous; SC, subcutaneous.

In patients who have contraindications to anticoagulation, the treatment algorithm will vary, depending upon the location of the original DVT (Fig. 12-3).

Fig 12–3 Treatment algorithm for deep venous thrombosis (DVT).

Long-Term Antithrombotic Therapy

The purpose of long-term anticoagulation is the prevention of recurrent VTE. The recommended duration of anticoagulation is outlined in Table 12-3.

 TABLE 12–3 Recommended Duration of Anticoagulation

This assumes that the patient has received a 5- to 10-day course of parenteral medications.

ACCP, American College of Chest Physicians; DVT, deep venous thrombosis; LE, lower extremity; LMWH, low-molecular-weight heparin; SC, subcutaneous; VTE, venous thromboembolism.

Adapted from Kearon C, et al. Antithrombotic therapy for venous thromboembolic disease. American College of Chest Physicians Evidence-Based Clinical Practice Guidelines (8th Edition). Chest 2008;133:454-545.

Thrombophilic Conditions: Inherited and Acquired

Clinical Presentation

Approximately 35% to 46% of patients with SVT are males (average age 54 years). The average age for females is about 58 years.^9,10 Factors associated with SVT include varicose veins (most frequent), age older than 60 years, obesity, tobacco use, and a history of DVT or SVT. Factors associated with extension of SVT include age older than 60 years, male sex, and a history of DVT. SVT of the great saphenous vein (GSV) is most common; however, SVT of the small saphenous vein (SSV) should not be overlooked because it may progress to popliteal DVT.

Etiology

To determine whether a hypercoagulable state contributes to the development of SVT, a number of markers were determined in a population of patients with acute SVT.¹¹ All patients had a coagulation profile performed that included (1) protein C antigen and activity, (2) activated protein C (APC) resistance, (3) protein S antigen and activity, (4) antithrombin (AT), and (5) lupus-type anticoagulant. Among 29 enrolled patients, 12 (41%) were found to have abnormal results consistent with a hypercoagulable state. Five of the patients (38%) with combined SVT/DVT and seven of the patients (44%) with isolated SVT were found to be hypercoagulable. These findings suggest that patients with SVT are at an increased risk of having an underlying hypercoagulable state.

Diagnosis

The physical diagnosis of superficial thrombophlebitis is based on the presence of erythema and tenderness in the distribution of the superficial veins, with the thrombosis identified by a palpable cord.

Duplex ultrasound scanning is now the initial test of choice for the evaluation of SVT as well as the diagnosis of DVT. The extent of involvement of the deep and superficial systems can be accurately assessed with this modality because routine clinical examination may not be able to precisely evaluate the proximal extent of involvement in either system.

Duplex imaging has shown concomitant DVT to be present in 5% to 40% of patients with SVT.^12–14 It is important to note that up to 25% of these DVTs may not be contiguous with the SVT and may be in the contralateral lower extremity.

Treatment

The goals of treatment are two-fold: reduction in local symptoms and prevention of thrombus propagation into the deep venous system. Frequently used treatment options include:

The progression of isolated SVT to DVT has been evaluated. Among 263 patients with isolated SVT by duplex ultrasonography, 30 (11%) patients had documented progression to deep venous involvement.¹⁵ Progression from the GSV in the thigh into the common femoral vein (21 patients) was most common, with 18 of these extensions noted to be nonocclusive and 12 having a free-floating component.

Because of the recognized potential for extension into the deep system and embolization, high saphenous ligation with or without stripping is often recommended for SVT within 1 cm of the SFJ. In a series of 43 patients who underwent ligation of the SFJ with and without local CFV thrombectomy and stripping of the GSV, two patients were found with postoperative contralateral DVT, one of whom had a PE^16–19 (Figs. 12-4 through 12-6).

Ligation was initially proposed to avert the development of DVT by preventing extension through the SFJ. Since issues of noncontiguous DVT and postligation DVT with PE are not addressed by this therapy, alternative treatment options need to be explored.

A prospective nonrandomized study was conducted to evaluate the efficacy of anticoagulation in the management of SFJ thrombophlebitis (SFJT).²⁰ Duplex ultrasonography was performed before admission, both to establish the diagnosis and to evaluate the deep venous system. Patients were hospitalized, given a full course of heparin treatment, and evaluated with duplex ultrasound 2 to 4 days after admission. Patients with SFJT alone and resolution of SFJT as documented by duplex ultrasound scans were maintained on warfarin for 6 weeks. Those patients with SFJT and DVT were maintained on warfarin for 6 months. Among 20 enrolled patients, 8 (40%) had concurrent DVT, including 4 with unilateral DVT, 2 with bilateral DVT, and 2 with development of DVT despite anticoagulation. DVT was contiguous with SFJT in 5 patients and noncontiguous in 3 patients. Seven of 13 duplex ultrasound scans obtained at 2 to 8 months’ follow-up demonstrated partial resolution of SFJT, 5 had complete resolution, and 1 demonstrated no resolution. There were no episodes of PE, recurrence, or anticoagulation complications at maximum follow-up of 14 months. Anticoagulation therapy to manage SFJT was effective in achieving resolution, preventing recurrence, and preventing PE within the follow-up period.

Meta-analysis of surgical versus medical therapy for isolated above-knee SVT has been attempted but has not been feasible because of the paucity of comparable data between the two groups.²¹ This review suggested that although stripping provides superior symptomatic relief, medical management with anticoagulants is somewhat superior with respect to minimizing complications and preventing subsequent DVT and PE. Based on these data, the authors suggest that anticoagulation is appropriate in patients without contraindications.

Although proximal GSV SVT occurs frequently, the best treatment regimen based on its underlying pathophysiology and resolution rate remains controversial. More recent investigations do offer some guidelines suggesting that anticoagulation is more effective than venous ligation in preventing DVT and PE.²² Further examination of the unresolved issues involving SVT is fundamental.

EHIT (endothermal heat-induced thrombosis) was briefly covered in Chapter 5. The following is a typical example of the natural course of an SFJT after thermal ablation treatment. This series of ultrasounds demonstrates a generous thrombus at SFJ retracting over time from postoperative day 3 (initial ultrasound) to postoperative day 5, where retraction has begun. At 3 weeks postoperative, the thrombus extension is no longer visualized. No anticoagulation or platelet therapy was used. Notice that no contiguous thrombotic lesions were identified in the deep system. This situation is very different from the ultrasound and CT scans shown previously (see Figs. 12-4 through 12-6), in which case the patient presented with spontaneous GSV thrombosis extending into the SFJ and developed a PE (Fig. 12-7).

Fig 12–4 Superficial venous thrombosis: thrombus at saphenofemoral junction extends into common femoral vein.

Fig 12–5 Pulmonary artery embolus to left lower lobe (cross-sectional view).

Fig 12–6 Pulmonary artery embolus to left lower lobe (sagittal view).

Fig 12–7 A, Thrombus extension (EHIT) seen on postoperative day 3 at the saphenofemoral junction. B, Fully compressed femoral vein (left panel) demonstrating no femoral vein thrombosis. C, Fully compressed popliteal vein (right panel) demonstrating no evidence of popliteal vein thrombosis. D, Onset of thrombus retraction (EHIT) seen on postoperative day 5. E, Completely retracted thrombus extension (EHIT) seen postoperatively at 3 weeks.