Christopher Kabrhel
EPIDEMIOLOGY
Venous thromboembolism (VTE) includes two main disease entities: deep vein thrombosis (DVT) and pulmonary embolism (PE).
There are approximately 2 million cases of VTE diagnosed in the United States every year.
Between 1 to 2/1000 emergency department (ED) patients are diagnosed with
PE annually. PE is the third most common cause of cardiovascular death in the United States, with an annual incidence similar to stroke. However, approximately 18 ED patients are evaluated for possible PE for every PE diagnosed, making negative workups for PE extremely common.
Major risk factors for VTE include advanced age (>50 years), venous stasis, hypercoagulable states, and endothelial injury (Table 27-1).
Venous stasis may result from general immobility (eg, obesity, sedentary lifestyle, neurologic disorders, debilitating illness, general anesthesia) or limb immobility (eg, trauma, surgery, neurologic paralysis).
Hypercoagulable states may be inherited (eg, factor V Leiden, prothrombin 20210A mutation, protein C or S deficiency) or acquired (eg, malignancy, pregnancy, estrogen use, antiphospholipid antibody syndrome).
TABLE 27-1 Risk Factors for Venous Thromboembolism (VTE) that are Generally Relevant to Emergency Medicine
Endothelial injury may be a result of trauma, surgery, vascular access, indwelling catheters, or prior deep venous thrombosis (DVT).
PATHOPHYSIOLOGY
DEEP VEIN THROMBOSIS
DVT forms most commonly at the venous cusps of deep veins and at sites of endothelial injury, though DVT may also propagate from thrombosed superficial veins. Thromboses are composed mostly of erythrocytes, fibrin, and platelets.
The majority (90%) of DVT occur in the lower extremities, though thrombosis of the upper extremities can also occur, especially in the presence of indwelling venous catheters.
DVT may propagate, dissolve, or embolize, depending on the balance between thrombogenesis and throm-bolysis.
Most (80%) symptomatic DVT will be located in or proximal to the popliteal vein, though 20% of isolated calf DVT will extend proximally within a week of diagnosis.
Proximal DVTs are more likely to cause PE than distal DVT.
PULMONARY EMBOLISM
PE occurs when a portion of a venous clot breaks off, traverses the right ventricle, and lodges in a pulmonary artery.
The pathophysiologic effects of PE are the result of mechanical obstruction of right ventricular outflow and the release of inflammatory mediators from thrombus in the pulmonary vasculature.
Depending on the degree of mechanical obstruction, PE may cause minimal symptoms, tachycardia, right heart failure, or complete cardiovascular collapse.
The mechanism of the dyspnea and hypoxia in PE is unclear and unpredictable. It is likely related to V/Q mismatch caused by vasoactive mediators combined with the relative shunting of blood away from oxygenated alveoli.
CLINICAL FEATURES
DEEP VEIN THROMBOSIS
The classic symptoms of DVT include calf or leg pain, redness, swelling, tenderness, and warmth. Unfortunately, fewer than 50% of patients with confirmed lower extremity DVT present with these symptoms, making the clinical examination for DVT challenging.
The signs and symptoms of DVT may also be seen with cellulitis, congestive heart failure, venous stasis without thrombosis, ruptured Baker’s cysts, and mus-culoskeletal injuries. DVT may also coexist with these entities. Thus, ruling out DVT without diagnostic testing can be challenging.
Homans’ sign, pain in the calf with forced dorsiflex-ion of the ankle with the leg straight, is unreliable for DVT.
Uncommon but severe presentations of DVT include phlegmasia cerulea dolens and phlegmasia alba dolens.
Phlegmasia cerulea dolens is a high-grade obstruction that elevates compartment pressures and can compromise limb perfusion. It presents as a massively swollen, cyanotic limb.
Phlegmasia alba dolens is usually associated with pregnancy and has a similar pathophysiology but presents as a pale limb secondary to arterial spasm.
PULMONARY EMBOLISM
The clinical presentation of PE varies considerably. Patients with similar co-morbidities and clot burden can present very differently.
PE should be suspected in patients with dyspnea unexplained by findings on auscultation, ECG, or chest x-ray.
Common symptoms include dyspnea (the most common symptom, seen in 75% of PE patients) and chest pain (the second most common symptom, seen in 50% of PE patients). Chest pain may be pleuritic (worse with breathing or coughing). Other symptoms include cough, syncope, palpitations, and anxiety.
Approximately 30% of patients with demonstrated DVT, but no symptoms of PE, will have subclinical PE found upon further study.
Common signs include tachypnea, tachycardia, hypoxemia (Sa O2 <95% on room air), hemoptysis, diaphoresis, and fever (>38°C).
Signs of DVT (calf pain, tenderness, swelling, erythema) occur in about 50% of patients. DVT is diagnosed in only 40% of ambulatory patients with demonstrated PE.
Massive PE results in hypotension and severe hypoxia. Cardiac arrest occurs in about 2% of diagnosed PE, though it is estimated that 20% to 25% of sudden cardiac death may be secondary to PE.
DIAGNOSIS AND DIFFERENTIAL
PRETEST PROBABILITY ASSESSMENT
Estimating the patient’s pretest probability for VTE is the first step in selecting a diagnostic pathway. The importance of determining the pretest probability should not be underestimated.
Pretest probability can be subjectively determined by the clinician, though accuracy requires experience. Alternatively, clinical scores that incorporate symptoms, signs, and risk factors can group patients into low, intermediate, and high probability categories.
DEEP VEIN THROMBOSIS
Decision instruments, such as the scoring system developed by Wells and colleagues, have been developed to categorize patients as having low, moderate, or high probability of DVT before diagnostic testing (Table 27-2). The system is scored as follows: a score of 3 or more represents high probability; a score of 1 to 2 corresponds to moderate probability; and a 0 score indicates low probability.
TABLE 27-2 Wells Score for deep Vein Thrombosis
PULMONARY EMBOLISM
The pulmonary embolism rule-out criteria (PERC Rule) can be used to define a group of patients whose probability of PE is below the test threshold (ie, the risk of testing outweighs the risk of a missed PE) (see Table 27-3). When combined with a low clinical probability, a negative PERC rule reduces the likelihood of PE to about 1%. These patients need not undergo objective testing (eg, d-dimer) for PE.
TABLE 27-3 Pulmonary Embolism Rule-Out Criteria (PERC Rule)
Age <50
Pulse oximetry >94% (breathing room air)
Heart rate <100 beats/min
No prior venous thromboembolism
No recent surgery or trauma (requiring hospitalization, intubation, or epidural anesthesia within 4 wk prior)
No hemoptysis
No estrogen use
No unilateral leg swelling
For patients with non-low clinical probability or a positive PERC Rule, the pretest probability of PE guides the clinician’s choice of diagnostic modality and helps determine when it is safe to terminate ancillary testing.
For an experienced clinician, clinical gestalt and published clinical decision rules have similar accuracy for defining the pretest probability of PE. The PE scoring system developed by Wells is well validated and can categorize patients as having low, moderate, or high probability of PE (Table 27-4). The system is scored as follows: a score of 6 or more represents high probability; a score of 2 to 6 corresponds to moderate probability; and less than 2 score indicates low probability. A modified Wells score can also be used, with a score of greater than 4 defining high probability, and a score of less than or equal to 4 defining low probability.
TABLE 27-4 wells Score for Pulmonary embolism (Pe)
ANCILLARY TESTING
DEEP VEIN THROMBOSIS
Quantitative d-dimer assays are highly sensitive for DVT. Patients with a low pretest probability (eg, Wells DVT score ≤1) can be safely considered to be without DVT if the d-dimer result is negative. Patients with a positive d-dimer result should undergo venous ultrasound in the ED to rule out DVT.
Diagnostic algorithms can help guide appropriate diagnostic testing for DVT, though it is important to acknowledge that no diagnostic algorithm is perfect (see Fig. 27-1).
FIG. 27-1. Diagnostic algorithm for deep venous thrombosis (DVT). This algorithm is to be applied in patients with leg symptoms compatible with DVT + = positive test result; - = negative test result.
Venous ultrasonography is the imaging test of choice for evaluating DVT in the ED. Duplex ultrasonography (real time B-mode imaging combined with Doppler flow imaging) has high sensitivity (97%) and specificity (94%) for lower extremity DVT. Sensitivity is lower for pelvic and isolated calf DVT (73%), and for upper extremity DVT (56%-100%).
For patients with moderate or high pretest probability for DVT, both venous ultrasound and d-dimer testing should be performed.
If both tests are negative, DVT can be considered ruled-out in the ED, with no further testing necessary.
If the ultrasound is negative but d-dimer is positive, a repeat ultrasound should be scheduled for a week later. Two negative duplex scans 1 week apart translate into a risk of <1%, for DVT or PE within 3 months. Several studies have demonstrated the safety of withholding anticoagulation pending repeat evaluation.
A positive ultrasound confirms the diagnosis of DVT (Fig. 27-2).
FIG. 27-2. Compression venous US images showing normal findings and findings indicating deep venous thrombosis. A. Compression venous US of the common femoral vein and femoral artery. The left view shows a sonographic image of the right femoral artery (A) and common femoral vein (V) obtained immediately inferior to the inguinal ligament. The image on the right shows the same view after manual compression by the operator. The image demonstrates obliteration of the vein while the artery remains open. This is a normal US finding for the vein. B. Venous US image showing evidence of common left femoral vein thrombosis after compression (right panel). The common femoral vein (V) does not compress. Echogenic thrombolytic material can be observed within the vein.
The traditional gold standard for DVT is contrast venography. However, the technique is invasive and impractical, and thus rarely performed. Other tests, such as CT and MRI venography, may be useful in diagnosing DVT when ultrasound cannot be performed or when pelvic vein thrombosis is suspected. However, the diagnostic accuracy of these tests is not well defined, and availability in the ED may be limited.
PULMONARY EMBOLISM
Most patients presenting with symptoms/signs suggestive of PE will undergo basic cardiopulmonary testing including electrocardiography (ECG), pulse oximetry, and chest radiography. However, these tests are insensitive and nonspecific for PE.
The classic EKG findings of an S wave in lead I, a Q wave in lead III, and T-wave inversions in lead III (S1 Q3 T3) are seen in a minority of PE patients.
Chest radiographs are typically normal or nonspecific in PE. Classically described findings such as Westermark’s sign and Hampton’s hump are infrequently seen.
Arterial blood gas testing (ABG) cannot be used alone to diagnose or exclude PE. The sensitivity of an abnormal Pa O2 or A-a gradient for PE is about 90%; specificity of either of these findings is only 15%.
Diagnostic algorithms can help guide appropriate diagnostic imaging for PE, though it is important to acknowledge that no diagnostic algorithm is perfect (Fig. 27-3).
FIG. 27-4. Axial image from a chest CT angiogram demonstrating a filling defect consistent with acute pulmonary embolism. Two white arrowheads outline a circular filling defect in the right middle lobar pulmonary artery. The long white arrow projecting in the left lung points to a filling defect in a segmental artery in the posterior medial segmental artery.
d-dimer testing is an important adjunct in exclusion of PE. d-dimers are released into the blood as fibrin clot is degraded. d-dimer assays differ in their test characteristics, so it is important to understand the type of d-dimer assay being used. The diagnostic sensitivity of automated quantitative d-dimer assays is typically between 94% and 98% and the specificity is typically between 50% and 60%. Accordingly, a negative d-dimer can rule-out PE in patients with low or intermediate pretest probability of PE.
The ability to rule out PE with d-dimer testing is limited by the large percentage of false positives. Many risk factors for PE (eg, advanced age, malignancy, pregnancy, recent surgery or trauma, immobility) also predispose to false positive d-dimer results, d-dimer testing should be used in select patients likely to have a negative result.
Patients with positive d-dimer results should be followed by confirmatory imaging unless concurrent testing has yielded an obvious alternative diagnosis.
CT pulmonary angiography portrays a clot as a filling defect in contrast-enhanced pulmonary arteries (see Fig. 27-4).
FIG. 27-3. Charlotte diagnostic algorithm for pulmonary embolism (PE). *Some physicians prefer to start with a clinical decision rule such as the Wells score (where <2, 2–6, and >6 are used instead of <15%, 15%-40%, and >40%, respectively). Note: Renal function should be determined by clinical picture (healthy, no risk factors for reduced glomerular filtration rate [GFR]) or calculated using known formulas. Nondiagnostic ventilation-perfusion (V/Q) scan findings require confirmation from results of another test, such as CT pulmonary angiography (CTPA), if benefits outweigh risks. + = positive for PE; - = negative for PE; Cr = creatinine; high = high probability scan findings; LMWH = low-molecular-weight heparin; Nl = normal; Nondx = nondiagnostic (any reading other than normal or high probability); PERC = pulmonary embolism rule-out criteria; quant = quantitative.
Images are obtained in 1.25 to 3.0-mm slices from the diaphragm to the apex of the lung.
This may be followed by indirect venography to evaluate the lower extremity vasculature.
The diagnostic sensitivity and specificity of a technically adequate CT scan, performed on a multidetector CT scanner in an ED population independently of pretest probability, is about 85% to 90%.
CT pulmonary angiography has the advantage of demonstrating alternative diagnoses in about 20% of studies in which no PE is found.
CT pulmonary angiography carries risks of radiation exposure, anaphylactoid reactions to contrast dye, and contrast-induced nephropathy; it is contraindicated in patients with impaired renal function.
Ventilation-perfusion (V/Q) scanning compares the density of scintillations emitted from radionucle-otides injected during a perfusion phase to those inspired during a ventilation phase.
A V/Q scan that demonstrates homogeneous scintillation throughout the lung in the perfusion portion has nearly 100% accuracy for ruling out PE, regardless of the appearance of the ventilation portion.
A V/Q scan that demonstrates two or more apex central wedge-shaped defects in the perfusion phase with normal ventilation in these regions indicates >80% probability of PE.
All other V/Q scan findings are nondiagnostic.
Catheter-based pulmonary angiography is the traditional gold-standard diagnostic test for PE, but this test requires expertise and carries risks associated with contrast and radiation exposure, dysrhythmias, and pulmonary artery perforation. It has been largely supplanted by CT pulmonary angiography.
Lower extremity venous ultrasound can be accomplished at the bedside and without ionizing radiation. However, venous US has a sensitivity of only 40% as a surrogate method to diagnose PE. Venous ultrasound can be a useful adjunct in patients with symptoms/signs of PE who have contraindications to CT pulmonary angiography (eg, pregnancy, renal insufficiency).
PE remains a common cause of pregnancy-related mortality and special consideration should be given to the evaluation of PE in these patients.
For pregnant patients undergoing V/Q scanning, Foley catheter placement and IV hydration can reduce fetal exposure to ionizing radiation.
In the case of a normal perfusion scan, the ventilation phase of the study can be avoided, thus limiting radiation exposure.
For pregnant patients undergoing CT scanning, lead shielding may decrease fetal radiation exposure.
With appropriate precautions in place, V/Q and CT probably expose the fetus to similarly low levels of ionizing radiation and should be considered safe techniques.
EMERGENCY DEPARTMENT CARE AND DISPOSITION
BASIC ED CARE
As always, attention to airway stabilization, respiratory and circulatory support is paramount. Administer crystalloid IV fluids to augment preload and correct hypotension. Administer oxygen as necessary to correct hypoxia secondary to PE.
ANTICOAGULATION
The specific objectives in treating VTE are to eliminate the clot burden and prevent recurrent thrombosis and embolization.
Anticoagulation with a form of heparin is standard ED treatment for most cases of VTE. Heparin therapy inhibits thrombin and prevents thrombus extension. Heparin has no intrinsic thrombolytic activity, but by allowing unopposed action of plasmin, it accelerates clot removal over 48 to 72 hours.
Low molecular weight heparins (LMWH) are safe and effective for the treatment of DVT. The three most commonly used LMWHs are dalteparin (200 units/kg subcutaneously every 24 hours, maximum 18,000 units), enoxaparin (1.5 milligrams/kg subcutaneously every 24 hours, maximum 180 milligrams), and tinzaparin (175 units/kg subcutaneously every 24 hours, maximum 18,000 units).
There are no treatment guidelines for thromboses isolated to the calf veins (soleal or gastrocnemius) or the saphenous vein. Isolated calf vein thrombosis has been reported to have varying risk levels of PE; estimates for PE development in these cases range from 0.3% to 8.0%. Options include no acute treatment with repeat US in a week to identify progression of clot, and outpatient treatment with LMWH.
Systematic reviews also favor the use of LMWH over unfractionated heparin (UFH) for treatment of PE, although the magnitude of benefit is not large. However, LMWH should be avoided in severe renal insufficiency and when absorption may be unreliable (eg, obesity).
When UFH is used, dosing should be weight based, with 80 units/kg given as an initial bolus followed by 18 units/kg/h. The activated partial thromboplastin time (aPTT) should be maintained between 55 and 80 seconds (1.5–5.2 times normal). Traditional dosing using a 5000-units bolus and 1000 units/h infusion will underdose two-thirds of patients.
There are few absolute contraindications to anticoagulation with heparin for acute VTE, though patients with recent intracranial hemorrhage or active gastrointestinal hemorrhage may have anticoagulation withheld.
For patients with documented heparin-induced throm-bocytopenia (HIT), a direct thrombin inhibitor or factor Xa inhibitor may be considered.
Oral anticoagulation with warfarin can be initiated simultaneously with heparin therapy. However, because of a transient hypercoagulable state caused by a relative deficiency in protein C in the first days of warfarin therapy, treatment should always be accompanied by heparin anticoagulation. Initial dosing of warfarin is usually 5 milligrams/day with a target INR of 2 to 3. Anticoagulation is typically continued for 3 to 6 months, but may be life-long in patients with persistent risk factors. Warfarin is absolutely contraindicated in pregnancy.
THROMBOLYSIS
Thrombolytic therapy should be considered for patients who require more aggressive treatment for VTE.
For DVT, there is no evidence showing a survival benefit of thrombolytic therapy over heparin and warfarin.
DVT that causes phlegmasia can lead to loss of limb. In these cases, catheter-directed thrombolysis should be discussed with an interventional radiologist or vascular surgeon. If no such service is available, and emergency transfer cannot be arranged, systemic thrombolysis should be considered if there are no absolute contraindications. A total IV dose of 50 to 100 milligrams of tPA (alteplase) infused over four hours is suggested, with this dosing based upon case series and limited clinical trials.
Patients who might realize substantial benefit from active thrombolysis are those with significant iliofemoral clot burden, those with acute phlegmasia (symptom onset <10 days) requiring aggressive and urgent intervention to decrease compartment pressures, and patients with occluded veins as a result of May-Thurner (iliac vein compression) syndrome.
Currently, the only patients with a demonstrated mortality benefit from thrombolytic therapy are those with massive PE, defined as a large PE associated with hemodynamic instability.
Thrombolysis also does not appear to reduce mortality in submassive PE, defined as near-normal blood pressure with other evidence of cardiovascular strain (eg, echocardiographic evidence of right ventricular dysfunction, positive troponin, elevated brain natriu-retic peptide). However, these patients may benefit from thrombolytic therapy in terms of functional capacity and quality of life.
Best-evidence practice is consideration of systemic fibrinolysis only in the following carefully selected patients as long as there is no increased risk of bleeding: patients with cardiac arrest at any point; patients with arterial hypotension and massive PE; patients with respiratory failure, evidenced by severe hypoxemia despite oxygen administration together with evidence of increased work of breathing; and patients with evidence of right-sided heart strain on echocardiogra-phy or elevated levels of troponin.
The FDA has approved three regimens for treatment of PE: streptokinase, urokinase, and tissue plasmino-gen activator (tPA). The recommended dosage of tPA, or alteplase, for PE is 100 milligrams infused over 2 hours. However, in emergent cases where a 2-hour infusion is impractical, 100 milligrams of tPA may be given as an off-label bolus over 10 to 15 minutes.
ADJECTIVE THERAPY
An inferior vena cava filter can be placed to prevent PE when anticoagulation is contraindicated, a major complication occurs, or when DVT continues to propagate despite adequate anticoagulation.
Surgical or catheter-based thrombectomy may be considered for patients with severe VTE (massive PE or DVT with persistently ischemic limb secondary to phlegmasia cerulea dolens). This procedure is typically only available in specialized centers.
DISPOSITION
Outpatient treatment of DVT is favored over inpatient treatment if the patient does not have complicating factors favoring admission. Admission should be considered in patients with: extensive iliofemoral thrombosis, increased risk of bleeding, limited car-diorespiratory reserve, risk of poor compliance with home therapy, a contraindication to use of LMWH, a high suspicion of HIT, or renal insufficiency.
Stable patients with PE can be admitted to a telemetry bed. Patients who exhibit signs of circulatory compromise and all patients who receive thrombolytic therapy should be admitted to an intensive care unit.
For further reading in Tintinalli’s Emergency Medicine: A Comprehensive Study Guide, 7th ed., see Chapter 60, “Thromboembolism,” by Jeffrey A. Kline.