Venous Thromboembolism

DEFINITION AND CAUSES

Venous thromboembolism (VTE) is a disease that includes both deep vein thrombosis (DVT) and pulmonary embolism (PE). It is a common, lethal disorder that affects hospitalized and nonhospitalized patients, recurs frequently, is often overlooked, and results in long-term complications including chronic thromboembolic pulmonary hypertension (CTPH) and the post-thrombotic syndrome (PTS).

Venous thromboembolism results from a combination of hereditary and acquired risk factors, also known as thrombophilia or hypercoagulable states. In addition, vessel wall damage, venous stasis, and increased activation of clotting factors first described by Rudolf Virchow more than a century ago still remain the fundamental basis for our understanding of thrombosis.

PREVALENCE AND RISK FACTORS

Venous thromboembolism is the third most common cardiovascular illness after acute coronary syndrome and stroke.¹ Although the exact incidence of VTE is unknown, it is believed there are approximately 1 million cases of VTE in the United States each year, many of which represent recurrent disease.² Nearly two thirds of all VTE events result from hospitalization, and approximately 300,000 of these patients die.³ Pulmonary embolism is the third most common cause of hospital-related death and it is the most common preventable cause of hospital-related death.^4,⁵ Most hospitalized patients have at least one or more risk factors for VTE (Box 1). Long-established and well-known cardiovascular risk factors including hypertension, diabetes mellitus, cigarette smoking, and high cholesterol levels have been linked to acute PE.⁶

PATHOPHYSIOLOGY AND NATURAL HISTORY

Venous thrombi, composed predominately of red blood cells but also platelets and leukocytes all bound together by fibrin, form in sites of vessel damage and areas of stagnant blood flow such as the valve pockets of the deep veins of the calf or thigh. Thrombi either remain in the peripheral veins, where they eventually undergo endogenous fibrinolysis and recanalization, or they embolize to the pulmonary arteries and cause PE.

Deep Venous Thrombosis

The lower extremities are the most common site for DVT, but other affected locations include the upper extremities and the mesenteric and pelvic veins. A proximal lower-extremity DVT (defined as the popliteal vein and above) has an estimated risk of 50% for PE if not treated; approximately 25% of calf vein thrombi propagate (in the absence of treatment) to involve the popliteal vein or higher.

Pulmonary Embolism

Pulmonary emboli commonly result from lower extremity DVTs. These thrombi have the potential to lead to a number of physiologic changes due to their obstruction of the pulmonary arteries. These include increased respiratory rate and hyperventilation, impairment of gas exchange due to impaired perfusion but not ventilation, intrapulmonary shunting leading to hypoxemia, and atelectasis and vasoconstriction resulting from the release of inflammatory mediators (serotonin and thromboxane).

In hemodynamically challenged patients, acutely elevated pulmonary vascular resistance results in decreased right ventricular (RV) output and hypotension. To overcome the obstructing thrombus and maintain pulmonary perfusion, the right ventricle must generate systolic pressures in excess of 50 mmHg and mean pulmonary artery pressures greater than 40 mmHg.⁷ The normal right ventricle, however, is unable to generate these pressures, and right heart failure and cardiac collapse ensues. Additionally, elevated RV wall tension can lead to decreased right coronary artery flow and ischemia. Cardiopulmonary collapse from PE is more common in patients with coexisting coronary artery disease or underlying cardiopulmonary disease .⁸

OUTCOMES

Close to 30% of patients who have an acute DVT develop the PTS by year 8 following their initial episode.⁹ Most develop signs and symptoms of this condition within 2 years of their acute event, and nearly 25% develop a chronic venous stasis ulcer.

Of the approximately 300,000 Americans who have a fatal PE each year, as many as 15% to 25% present with sudden death or die within 30 days of their diagnosis.¹⁰ The majority of patients die because of a failure in diagnosis rather than inadequate therapy. In fact, the mortality rate for PE without treatment is approximately 30%, whereas it is only 2% to 8% with adequate therapy.¹¹ In addition, nearly 4% of all PE patients develop CTPH by the second year following their event.¹²

SIGNS AND SYMPTOMS

Deep Venous Thrombosis

Typical symptoms of DVT in the upper and lower extremities include pain or tenderness and swelling. Signs on physical examination include increased warmth, edema, and erythema and the presence of dilated veins (collaterals) on the chest wall or leg. A limb-threatening manifestation of DVT, phlegmasia cerulea dolens, occurs most often in the setting of malignancy, heparin-induced thrombocytopenia (HIT), or other thrombophilic conditions in which the thrombus completely occludes venous outflow, causing massive limb swelling, hypertension in the capillary bed, and eventually ischemia and gangrene if untreated.

Pulmonary Embolism

The most common signs and symptoms of acute PE include dyspnea, tachypnea, and pleuritic chest pain.¹³ Other reported findings include apprehension, hemoptysis, cough, syncope, and tachycardia. Fever, gallop heart sounds (S₃ and/or S₄), accentuation of the pulmonary closure sound, rales, and leg erythema or a palpable cord may also be found.

DIAGNOSIS

Deep Venous Thrombosis

Clinical Decision Rules

The clinical examination of DVT is often unreliable; therefore, clinical decision rules (pretest probability scores) based on the patient’s signs, symptoms, and risk factors have been developed to stratify patients into low, moderate, or high clinical probability.^14,¹⁵^–¹⁸ This approach helps to improve the effectiveness of diagnosing DVT as well as limiting the need for additional testing. Using the clinical decision rule (Table 1), patients in the low pretest probability category have a 96% negative predictive value for DVT (99% if the D dimer is negative as well), and the positive predictive value in patients with a high pretest probability is less than 75%, supporting the need for further diagnostic testing to identify patients with an acute thrombosis.¹⁵^–¹⁸

Table 1 Pretest probability of Deep Venous Thrombosis (Wells score)⁵⁶

Clinical Feature*	Score
Scoring
Active cancer (treatment ongoing or within previous 6 months of palliative treatment)	1
Paralysis, paresis, or recent plaster immobilization of the lower extremities	1
Recently bedridden for more than 3 days or major surgery, within 4 weeks	1
Localized tenderness along the distribution of the deep venous system	1
Entire leg swollen	1
Calf swelling by more than 3 cm when compared with the asymtpomatic leg (measured 10cm below tibial tuberosity)	1
Pitting edema (greater in the symptomatic leg)	1
Collateral superficial veins (not varicose)	1
Alternative diagnosis as likely or greater than that of deep-vein thrombosis	−2
Analysis
High	≥3
Moderate	1 or 2
Low	≤0
Modified Score (adds one point if there is a previously documented DVT
Likely	≥2
Unlikely	≤1

* In patients with symtpoms in both legs, the more symptomatic leg is used.

Pretest probability scores or clinical decision rules have also been developed to aid in the diagnosis of acute PE.²² (Table 2). This approach is similar to that employed for DVT; using signs, symptoms, and risk factors to calculate a low, moderate, or high pretest probability score. In a validation study using this approach in combination with a negative D dimer, only 0.5% of patients who were thought unlikely to have a PE later developed nonfatal VTE.²³

Table 2 Clinical Decision Rules (Pre-test Probability for Pulmonary Embolism)⁵⁶

Variable	Points
Clinical signs and symptoms of DVT (minimum of leg swelling and pain with palpation of the deep veins	3.0
Alternative diagnosis less likely than PE	3.0
Heart rate >100 bpm	1.5
Immobilization (>3 days) or surgery in the previous week	1.5
Previous PE or DVT	1.5
Hemoptysis	1.0
Malignancy (receiving treatment or treated in last 6 months or palliative)	1.0

Key: Low probability < 2.0; moderate probability 2.0-6.0; high probability ≥6.0.

DVT, deep venous thrombosis; PE, pulmonary embolism.

Electrocardiography

The major utility of electrocardiography (ECG) in the diagnosis of PE is to rule out other major diagnoses, such as acute myocardial infarction (MI). The most specific finding on an ECG is the classic S₁Q₃T₃ pattern, but the most common findings consist of nonspecific ST-segment and T-wave changes. Other commonly reported but nonspecific findings include sinus tachycardia, atrial fibrillation, and right bundle-branch block.²⁴

Chest Radiography

Chest radiography may also be more helpful in establishing other diagnoses. The most common findings are nonspecific and include pleural effusion, atelectasis, and consolidation.

Arterial Blood Gas Determination

Pulmonary embolism can result in significant hypoxia, and in the Prospective Investigation of Pulmonary Embolism Diagnosis (PIOPED) study, only 26% of patients with angiographically proven PE had a PaO₂ greater than 80 mm Hg.²⁵ Therefore, a normal PaO₂ cannot rule out PE; however, hypoxia in the absence of cardiopulmonary disease should raise the suspicion for this diagnosis. In patients with cardiopulmonary collapse, a normal PaO₂ suggests an alternative diagnosis. Similarly, an elevated alveolar-arterial gradient is suggestive but not specific for the diagnosis of an acute PE. Therefore if the alveolar-arterial gradient is normal, an acute PE cannot be excluded.²⁶