Venous thromboembolism (VTE), including deep vein thrombosis (DVT) and pulmonary embolism (PE), is a common, preventable perioperative complication occurring in up to 5% of noncardiac surgical patients. Even when treated, DVT can lead to long-term consequences, including chronic edema, dermatitis, venous stasis ulcers, and post-thrombotic syndrome. Another complication of DVT, pulmonary embolism, carries 15% mortality, and acute phase survivors may develop pulmonary hypertension. Prevention and treatment of VTE are therefore exceedingly important.
Pathophysiology
The three mechanisms for venous thrombosis were originally described by Rudolph Virchow in 1856: hypercoagulability, stasis, and injured endothelium, known as Virchow triad. Initially, in response to endothelial injury or stasis, platelets begin aggregating and subsequently activate procoagulant factors while simultaneously inhibiting those that promote fibrinolysis. This process commonly begins in the calf veins, most notably the soleal vein, and almost exclusively occurs within the venous valves. More recent research has also focused on the role neutrophils play in clot formation.
Several risk factors, both inherited and acquired, can increase VTE risk. Common inheritable causes of hypercoagulable states include non-O blood group, deficiencies of protein C and protein S, factor V Leiden deficiency, antithrombin III deficiency, and prothrombin G20210A. In addition, methylene tetrahydrofolate reductase 677T and hyperhomocysteinemia also have increased risks of clotting. Both protein C and protein S are vitamin K–dependent natural anticoagulant proteins that are activated by thrombi via thrombomodulin and work in concert to inhibit the activation of factors V and VIII. When deficient, patients have a 10-fold increase in the risk of developing VTE. Factor V Leiden is a mutated form of factor V, which prevents protein C from binding and thereby leads to a procoagulant state. This can occur in both heterozygous and homozygous forms, the latter of which is associated with an incidence of venous thrombosis 80 times that of the general population. Antithrombin III is a protein that under normal conditions binds to and inactivates both factor II (thrombin) and factor X. Interestingly, deficiency of antithrombin III can be both inherited and acquired. The acquired form is associated with increased excretion as seen in renal failure, decreased production (which occurs in liver failure), and increased consumption as can happen in severe trauma. It may also be deficient after major surgeries, most specifically those requiring cardiopulmonary bypass. The prothrombin gene mutation (G20210A) leads to higher levels of prothrombin in the blood and therefore enhances the risk of clotting. The presence of antibodies to antiphospholipid also has a 10-fold higher risk of developing venous thrombosis. Finally, non-O blood groups express higher levels of FVIII and vWf conferring a smaller increase in VTE risk.
Acquired risk factors for the development of VTE are varied and consist of age greater than 40 years, prior VTE, varicose veins, malignancy, major surgery, increased surgical duration, prolonged anesthesia, trauma, sepsis, pregnancy, major fracture, obesity, prolonged immobility/paralysis, stroke, inflammatory bowel disease (IBD), estrogen use, and congestive heart failure, among others. Certain hematologic conditions can also create a hypercoagulable state and are associated with VTE. Examples are thrombotic thrombocytopenic purpura (TTP), hemolytic uremic syndrome (HUS), polycythemia vera, heparin-induced thrombocytopenia (HIT), and various other myeloproliferative disorders or malignancies. Although pregnancy is associated with an increased risk of VTE, men are more likely to develop recurrent VTE.
Prevention
The Caprini Score is a validated risk assessment tool developed to stratify patients into very low, low, moderate, and high-risk groups for developing DVT and thereby to guide the choice of prevention strategy. It designates point values to various risk factors, such as: age; type of surgery; body mass index (BMI); presence of malignancy, lung disease, cardiac disease (myocardial infraction, congestive heart failure), and IBD; stroke; hip, pelvis, or leg fracture; and inherited coagulopathies, among others. It then creates an estimate of VTE risk based on the total point value. It is important to note that this method was only validated for general, abdominal–pelvic, bariatric, vascular, and plastic/reconstructive surgery patients; however, it can be applied to other surgical populations. For patients who fall into the very low category, the risk of VTE without any prophylaxis is < 0.5%, and for those who fall into the high-risk category, this increases to 6%.
For patients who are at very low risk of VTE, the American College of Chest Physicians recommends neither mechanical nor chemoprophylaxis for DVT and instead suggests early ambulation as a means for prevention. For those at low risk of VTE, recommendations are to utilize mechanical prophylaxis alone. Mechanical prophylaxis includes both elastic compression stockings and sequential compression devices (SCDs). Compared with no prophylaxis, studies have demonstrated that elastic stockings reduce the rate of both asymptomatic and symptomatic DVT by 31%–65% but can be associated with skin complications. SCDs are intermittent pneumatic compression devices, which promote blood circulation through the veins of the legs, and have been shown to have a 60% reduction in the rate of VTE in various trials, although compliance can be difficult. Preference is usually for SCDs over compression stockings. Once patients enter the moderate and high-risk categories for VTE, chemoprophylaxis becomes the preferred method; however, the risk of bleeding must also be considered.
Patients at moderate to high risk of developing VTE should receive chemoprophylaxis as long as their risk of bleeding is acceptably low. Low molecular weight heparins (LMWHs; i.e., enoxaparin, dalteparin) and unfractionated heparin are the preferred agents for pharmacologic prevention based on guidelines. In high-risk patients, it is suggested to add mechanical prophylaxis. If patients are moderate to high risk but have a significant risk of bleeding, mechanical prophylaxis can be used as a sole agent until it is safe to start pharmacologic prophylaxis. If chemoprophylaxis is indicated but there are contraindications to either LMWH or unfractionated heparin (UFH), fondaparinux, dabigatran, or aspirin may be utilized instead.
Regular surveillance with Doppler ultrasound and prophylactic placement of inferior vena cava (IVC) filters have been described as methods of screening and prevention of VTE. They are not routinely recommended but remain a rare option.
Diagnosis
The Wells score is a validated tool used to assess the pretest probability of a patient having a DVT. It was initially studied in patients with a suspected first DVT and assigns point values to various clinical findings, such as recent immobility, localized tenderness, calf swelling, pitting edema, recent or active cancer, and stratifies patients into low, moderate, and high probability of DVT. The modified Wells score incorporates previous DVT into the algorithm and distinguishes patients as either unlikely or likely to have a DVT. Performance of diagnostic tests to confirm the presence of DVT should only be undertaken after determining a patient’s probability of having a DVT.
In patients for whom the Wells score identifies a low probability of DVT, recommendations are to perform a D-dimer test. A low D-dimer level effectively rules out the possibility of a DVT. If the D-dimer is elevated or if the patient would be expected to have an elevated D-dimer for any other reason, ultrasonography should be performed. In those with moderate probability of DVT, D-dimer is nonspecific and ultrasound is preferred.
Diagnosis of Deep Vein Thrombosis
Doppler ultrasound is now the most common tool for detecting DVTs, because it is highly accurate in detecting symptomatic DVT (sensitivity of 93% for acute, symptomatic, below the knee DVT), noninvasive, and easily repeatable. Its sensitivity and specificity are much less for asymptomatic DVT but it still remains the test of choice. Ultrasonic findings suggestive of acute DVT are enlarged affected veins, lack of intraluminal echoes, reduced compressibility, and lack of significant collaterals.
According to the American College of Chest Physicians Guidelines, contrast venography, which involves injecting contrast into a foot vein and observing proximal filling, is the gold standard for diagnosing DVT. However, given its cost, invasive nature, need for contrast, and overall limited availability, it is not commonly used. An alternative to this is CT venography, which similarly injects contrast to evaluate leg vein filling, but instead utilizes an arm vein for the injection site.
Other, now outdated, tests for diagnosis of DVT include radiolabeled fibrinogen uptake testing and impedance plethysmography.
Diagnosis of Pulmonary Embolism
The method of diagnosis for pulmonary embolism depends on the clinical presentation of the patient as well as the pretest probability of the patient having a PE. For those who are hemodynamically unstable, recommendations favor initial resuscitation, intubation, and mechanical ventilation as needed; transthoracic echocardiography may note signs of right ventricle (RV) strain or failure. If the patient is at high risk of PE, empiric anticoagulation is suggested. In patients at low or moderate risk of PE who are successfully resuscitated, guidelines suggest following the same approach at definitive diagnosis used for those who present with initial hemodynamic stability. Finally, for patients in whom hemodynamic stability cannot be obtained and a definitive diagnosis is not possible, a presumptive diagnosis of PE can be made based on the presence of RV strain on echocardiogram or DVT on lower extremity compression ultrasonography.
Pretest probability is important to consider not only for DVT, but also PE. The Wells score or Modified Wells score can be used and in outpatients further supplemented by the Pulmonary Embolism Rule-out Criteria (PERC) rule, which evaluates the likelihood of PE in patients with a Wells score < 2. This can help identify patients for whom the risk of testing for PE outweighs the risk of PE and consists of eight criteria: age < 50 years, pulse < 100, oxygen saturation of 95% or higher, no hemoptysis, no estrogen use, no prior DVT or PE, no unilateral leg swelling, and no surgery or trauma requiring hospitalization in the preceding 4 weeks.
A V/Q scan detects PE in approximately one-third of patients with the disease. In order to diagnose PE, there must be a segmental or subsegmental perfusion defect with normal ventilation. Although a highly sensitive test (98%), it has poor specificity (10%) and is not considered the gold standard for diagnosis. However, it can be valuable in patients in whom CT angiogram is contraindicated (i.e., contrast allergy, renal failure) or inconclusive.
CT pulmonary angiogram (CTPA) is the gold standard for diagnosing PE. A positive CTPA will demonstrate a filling defect within the pulmonary arteries. It is both sensitive and specific (> 90%) and also allows alternative diagnoses to be discovered.
Pulmonary angiography is a historical test with inferior accuracy compared with CTPA and has increased procedural risk.
Magnetic resonance pulmonary angiography (MRPS) is rarely performed despite its high sensitivity and specificity because of the lack of technology and expertise and because of time constraints.
Treatment of Venous Thromboembolism
Choosing an anticoagulant requires consideration of many factors. Factors such as renal function, risk of bleeding, adverse reactions, ease of use, cost, and the need for monitoring should be considered. Table 26.1 lists the most common anticoagulants used as therapy for VTE, and Fig. 26.1 shows their location of action within the coagulation cascade. The rate of recurrent thrombosis without adequate anticoagulation is 29%–47%, but falls to 5%–7% if appropriate treatment is administered.
| Category | Medication | Use in DVT/PE | Route of Administration | Dose | Reversal | Renal Considerations | Special Considerations |
|---|---|---|---|---|---|---|---|
| Anti-thrombin Activation | Unfractionated Heparin | Prophylaxis, treatment | Subcutaneous (SC), Intravenous (IV) | Prophylaxis : 5,000 units SC every 12 or 8 hours Treatment : 80 units/kg or 5,000 unit bolus followed by infusion to maintain aPTT corresponding to heparin level of 0.3-0.7 IU/mL activity. SC treatment dosing also available | Protamine sulfate | Negligible | |
| Anti-thrombin activation, Factor Xa inhibition (Low molecular weight heparins) | Enoxaparin (Lovenox), | Prophylaxis, treatment | SC | Prophylaxis : 40 mg SC daily (for normal renal function) Treatment : 1 mg/kg SC BID or 1.5 mg/kg daily | Protamine sulfate provides partial reversal | Contraindicated in renal impairment | Preferred anticoagulant in pregnant patients or patients with cancerrelated DVT |
| Dalteparin (Fragmin) | Prophylaxis, treatment | SC | Prophylaxis : 5,000 units SC daily Treatment : 200 units/kg SC daily (max 18,000 units daily) | Protamine sulfate provides partial reversal | Contraindicated in renal impairment | ||
| Vitamin K Antagonism (VKA) | Warfarin (Coumadin) | Treatment | Oral | Varying doses to maintain INR 2-3 | Vitamin K, FFP, Prothrombin Complex Concentrate | Negligible | Requires monitoring of INR |
| Has many drug-drug interactions | |||||||
| COX inhibition | Aspirin | Prophylaxis | Oral | 81 mg PO daily | None | ||
| Factor Xa Inhibition | Fondaparinux (Arixtra) | Prophylaxis, treatment | SC | Prophylaxis : 2.5 mg SC daily Treatment : < 50 kg – 5 mg SC daily 50-100 kg – 7.5 mg SC daily > 100 kg – 10 mg SC daily | Recombinant Factor VIIa | Contraindicated if renal impairment | Prophylactic use contraindicated in patients < 50 kg |
| Rivaroxaban (Xarelto) | Treatment | Oral | 15 mg BID x 21 days, then 20 mg daily | Andexanet alpha | Requires dose adjustment in renal impairment | Not for use in pregnancy | |
| Apixaban (Eliquis) | Treatment | Oral | 10 mg BID x7 days, followed by 5 mg BID (2.5 mg daily after 6 mo) | Andexanet alpha | Requires dose adjustment in renal impairment | Not for use in pregnancy | |
| Edoxaban (Savaysa) | Treatment | Oral | 60 mg daily if > 60 kg 30 mg daily if < 60 kg (following 5-10 days of parenteral anticoagulation) | Likely andexanet alpha pending FDA approval | Requires dose adjustment in renal impairment | Not for use in pregnancy | |
| Betrixaban (Bevyxxa) | Prophylaxis | Oral | 160 mg initial dose following by 80 mg daily | Likely andexanet alpha pending FDA approval | Requires dose adjustment in renal impairment | No longer available in US | |
| Direct Thrombin Inhibition | Bivalirudin | Treatment | IV | 0.15-2 mg/kg/h, titrate to PTT 1.5-2 times normal | None | Utilized in patients with or at high risk for HIT | |
| Desirudin | Prophylaxis | SC | 15 mg SC every 12 hours | None | Requires dose adjustment in renal impairment | New warning against spinal/epidural hematoma has caused it to be discontinued in the US | |
| Argatroban | Prophylaxis, treatment | IV | 0.2-2 mcg/kg/h Titrate to aPTT 1.5-3x normal | None | Utilized in patients with or at high risk for HIT | ||
| Dabigatran (Pradaxa) | Treatment | Oral | 150 mg BID (following 7 days of parenteral AC) | Idarucizumab (Praxbind) | Contraindicated in renal impairment |
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