Thromboembolic Disease

INTRODUCTION

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Thromboembolic disease is derived from Virchow’s triad of alterations in blood flow, vascular endothelial injury, and alterations in constituents of the blood. Risk factors include antithrombin deficiency, protein C deficiency, protein S deficiency, factor V Leiden, prothrombin gene deficiency, non-O ABO blood group, dysfibrinogenemia, elevated factor VIII, elevated factor IX, elevated factor XI, hyperhomocysteinemia, cancer, antiphospholipid syndrome, infection, inflammatory disorders, nephrotic syndrome, obesity, smoking, trauma, surgery, immobilization, central venous catheter, pregnancy, hormonal therapy, and travel.¹

PATHOPHYSIOLOGY

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Acute pulmonary embolism (PE) causes physical obstruction of blood flow and release of humoral factors such as serotonin, thrombin, and histamine.² Hypoxic vasoconstriction leads to elevated pulmonary vascular resistance. Increased afterload consequently causes right ventricular dilation, hypokinesis, tricuspid regurgitation, and right heart failure.² Further dilation of the right ventricle causes leftward bowing of the intraventricular septum. This causes left diastolic dysfunction, with decreased left diastolic filling. Further dilation of the right ventricle causes cardiac ischemia due to decreased subendocardial perfusion.² Acute pulmonary embolism typically originates from deep venous thrombosis of the lower extremities. Locally, this thrombosis can progress and cause venous congestion and fluid sequestration. This can compromise oxygen delivery to the limb, causing edema, pain, and cyanosis.

ASSESSMENT

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The increased use of computed tomography (CT) for evaluation of pulmonary embolism has not shown to improve outcomes and is not cost effective.^3-9 Therefore, decision-making tools have been developed to determine patients who will be benefit from additional testing (Table 10-1)^10-12.

TABLE 10-1Predictive Criteria for Thromboembolic Disease

Modified Wells Criteria¹⁰	Geneva Criteria¹¹	PERC¹²
Clinical signs of DVT Alternative diagnosis less likely HR > 100 bpm Immobilization (> 3 d) or surgery in the last 3 wk Previous DVT Hemoptysis Cancer treated in last 6 mo Total: Low risk Intermediate risk High risk PE likely PE unlikely	3 3 1.5 1.5 1.5 1 1 0–1 2–6 > 6 > 4 ≤ 4	Previous DVT/PE HR 75–94 bpm HR > 94 bpm Surgery or fracture within last month Hemoptysis Active cancer Unilateral lower extremity pain Pain on lower limb, deep venous palpation, and unilateral edema Age > 65 y Total: Low probability Intermediate probability High probability	3 3 5 2 2 2 3 4 1 0-3 4–10 ≥ 11	Age < 50 y Initial HR < 100 bpm O₂ saturation > 94% RA No unilateral leg swelling No hemoptysis No surgery or trauma within the last 4 wk No history of VTE No estrogen use Total:	Yes = 0/No = 1 Yes = 0/No = 1 Yes = 0/No = 1 Yes = 0/No = 1 Yes = 0/No = 1 Yes = 0/No = 1 Yes = 0/No = 1 Yes = 0/No = 1 Score 0 = pretest probability <1 %

Modified Wells Criteria¹⁰

Geneva Criteria¹¹

PERC¹²

Clinical signs of DVT

Alternative diagnosis less likely

HR > 100 bpm

Immobilization (> 3 d) or surgery in the last 3 wk

Previous DVT

Hemoptysis

Cancer treated in last 6 mo

Total:

Low risk

Intermediate risk

High risk

PE likely

PE unlikely

1.5

0–1

2–6

> 6

> 4

≤ 4

Previous DVT/PE

HR 75–94 bpm

HR > 94 bpm

Surgery or fracture within last month

Hemoptysis

Active cancer

Unilateral lower extremity pain

Pain on lower limb, deep venous palpation, and unilateral edema

Age > 65 y

Total:

Low probability

Intermediate probability

High probability

5 2

0-3

4–10

≥ 11

Age < 50 y

Initial HR < 100 bpm

O₂ saturation > 94% RA

No unilateral leg swelling

No hemoptysis

No surgery or trauma within the last 4 wk

No history of VTE

No estrogen use

Total:

Yes = 0/No = 1

Score 0 = pretest probability <1 %

Low to intermediate risk or probability warrant further testing with d-dimer (negative < 500 ng/mL) and adjusted for ages 50 years or older to maintain sensitivity greater than 97% and increase specificity.³ Computed tomography angiography (CTA) or ventilation/perfusion (V̇/Q̇) scan is indicated for high risk or probability.

IMAGING STUDIES

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Chest radiographs have been used as an initial investigation for dyspnea, although they are not helpful in confirming the presence of pulmonary embolism. As per Prospective Investigation Of Pulmonary Embolism Diagnosis (PIOPED) II, chest CTA has become the gold standard in diagnosis of acute pulmonary embolism with a sensitivity and specificity of 96% and 95%, respectively.¹³ As per PIOPED I, V̇/Q̇ scan is typically reserved for patients who cannot tolerate chest CTA due to renal failure, obesity, or contrast allergy. It is best performed in patients with a normal chest radiograph and no underlying pulmonary disease. Ventilation/perfusion interpretation is shown in Table 10-2.¹⁴

TABLE 10-2Interpretation of Ventilation/Perfusion Study

High probability ≥ 80%	Intermediate probability 20–79%	Low probability < 20%	Normal
≥ 2 large mismatched segmental perfusion defects	1–2 large mismatched segmental perfusion defects	Nonsegmental perfusion defects such as cardiomegaly, enlarged aorta, enlarged hila, or elevated diaphragm	No perfusion defects

Sensitivity is 40% and specificity is 98% for a high-probability V̇/Q̇ scan.¹⁵ For a low-probability V̇/Q̇ scan, the sensitivity is 99% and specificity is 12%.¹⁵ The positive predictive value of a high-probability V̇/Q̇ scan is 100% and the negative predictive value of a low-probability V̇/Q̇ scan is 94%.¹⁵ The PIOPED III study suggested that magnetic resonance angiography (MRA) had a sensitivity of 78% and specificity of 96%, and MRA and magnetic resonance venography (MRV) had a sensitivity of 92% and specificity of 96%.¹⁶ Due to technical difficulties, it is often reserved if CTA and V̇/Q̇ scan are negative and suspicion is still high. Pulmonary angiography’s sensitivity and specificity have not been formally evaluated, but in addition to diagnosis, it can also be used to intervene. Lower extremity ultrasound can suggest the presence of thromboembolic disease, but cannot confirm the presence of pulmonary embolism.

TREATMENT

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Acute treatment is for 5 to 10 days. Long-term anticoagulation is for 3 months, and extended anticoagulation implies indefinite duration.¹⁷ The decisions regarding whether or not to anticoagulate, which anticoagulation treatment to use, and the duration are dependent on the scenario, risk of bleeding, and individual comorbidities, as seen in Tables 10-1, 10-2, 10-3.^17-116 Table 10-3 shows different scenarios and their corresponding treatments of choice. As per the CHEST guidelines, quality of evidence is graded as high (Level A), moderate (Level B), and low (Level C) with the strength of recommendation as strong (Grade 1) and weak (Grade 2).¹¹⁷ Table 10-4 shows factors that will affect the type of anticoagulation.

TABLE 10-3Clinical Scenarios of Thromboembolic Disease, Treatment, and Considerations

Scenario	Treatment	Considerations\Rationale
Deep venous thrombosis or pulmonary embolism and no cancer-associated risk for at least 3 mo	First choice: rivaroxaban, apixaban, or edoxaban (Grade 2B) Second choice: vitamin K antagonist (Grade 2B)	Similar risk reduction for recurrent VTE between NOAC vs VKA Less bleeding with NOAC vs VKA Similar risk reduction between VKA and LMWH in patients without cancer LMWH expensive and burdensome
Deep venous thrombosis or pulmonary embolism with cancer risk	First choice: LMWH (Grade 2B) Alternatives: VKA, dabigatran, rivaroxaban, and apixaban (Grade 2C)	Risk reduction for recurrent VTE greater for LMWH than for VKA Unknown risk reduction for recurrent VTE between NOAC and LMWH
If patient has decided to stop anticoagulation for thromboembolic disease	Aspirin over no aspirin (Grade 2B)	Not a reasonable alternative to anticoagulation but better than no aspirin in reducing recurrent VTE
Acute isolated distal DVT of lower extremities without symptoms or risk factor for extension	First choice: serial imaging for 2 wk over anticoagulation unless symptomatic (Grade 2C)	Low risk for extension: soleus or gastrocnemius vein thrombosis High risk for extension: positive d-dimer, > 5 cm length, > 7 mm in diameter, multiple veins, proximal veins, no reversible factors, active cancer, history of VTE, and inpatient status
Subsegmental pulmonary embolism without proximal pulmonary artery involvement or proximal DVT	Low risk for recurrence: clinical surveillance (Grade 2C) High risk of recurrence: anticoagulation (Grade 2C)	High false positive True positive if CTA good quality, multiple intraluminal defects, more proximal subsegment arteries, defects in more than 1 image or projection, defects surrounded by contrast, symptomatic, high clinical probability, and d-dimer elevated High risk of recurrence if hospitalized or reduced mobility, active cancer, and no reversible risk factor for VTE
Acute pulmonary embolism with low risk of bleeding and hypotension	First choice: thrombolytics (Grade 2B)	Faster resolution of thromboembolism but mortality benefit uncertain Higher risk of ICH compared to anticoagulation
Acute pulmonary embolism, low risk of bleeding, no hypotension, but with evidence of cardiopulmonary deterioration such as symptoms, tissue hypoperfusion, worsening gas exchange, or cardiac markers, or worsened after initial anticoagulation	First choice: thrombolytics (Grade 2C)
Acute pulmonary embolism with hypotension, high risk of bleeding and failed thrombolytics	First choice: Catheter-assisted thrombus removal (Grade 2C)
Upper extremity DVT involving axillary or more proximal vein	First choice: anticoagulation (Grade 2C)	Thrombolytics indicated for most of subclavian and axillary vein, symptoms < 14 d, good functional status, life expectancy > 1 y, and low risk of bleeding
Recurrent venous thrombosis on VKA, dabigatran, rivaroxaban, apixaban, or edoxaban	First choice: LMWH (Grade 2C)	LMWH associated with higher risk reduction in VTE compared to VKA
Recurrent venous thrombosis on LMWH	First choice: increase LMWH by one-half to one-third (Grade 2C)