Epidemiology
A quiet revolution has occurred in the field of venous thromboembolism (VTE), which encompasses deep venous thrombosis (DVT) and pulmonary embolism (PE). VTE is no longer an orphan disease. Its adverse public health impact has been acknowledged in the United States by the National Quality Forum, the Joint Commission for Accreditation of Hospitals, the National Comprehensive Cancer Network, and the Surgeon General's Office. Public service announcements have educated laypersons on the definition and medical consequences of DVT and PE, along with risk factors and warning signs. VTE-related deaths in the United States are estimated at 300,000 annually: 7% diagnosed with VTE and treated, 34% sudden fatal PE, and 59% as undetected PE. Approximately two-thirds of symptomatic VTE events are hospital acquired, and the remainder are community acquired. Residents of skilled nursing facilities are especially vulnerable. The most recent estimates of hospitalized patients at risk for VTE in the United States total 13.4 million (M) patients annually: 5.8 M surgical patients at moderate–high risk and 7.6 M medical patients with comorbidities such as heart failure, cancer, and stroke. These new data provide the rationale for changing the prophylaxis paradigm from voluntary to mandatory compliance with guidelines to prevent VTE among hospitalized patients.
VTE is also a major European health problem, with an estimated 370,000 per year PE-related deaths, when data in France, Germany, Spain, Italy, Sweden, and the United Kingdom are combined. The estimated direct cost for VTE-associated care in Europe exceeds 3 billion euros per year.
Though DVT and PE encompass one disease entity, VTE, there are important differences. DVT occurs about 3 times more often than PE. The major adverse outcome of DVT alone, without PE, is the development of postphlebitic syndrome, which occurs in more than half of patients with DVT. Postphlebitic syndrome is a late adverse effect of DVT that is caused by permanent damage to the venous valves of the leg, which become incompetent and permit abnormal exudation of interstitial fluid from the venous system. It may not become clinically manifest until several years after the initial DVT. There is no effective medical therapy for this condition, which impairs quality of life and disables. Most patients describe chronic ankle swelling and calf swelling and aching, especially after prolonged standing. In its most severe form, postphlebitic syndrome causes skin ulceration, especially in the medial malleolus of the leg. PE can be fatal or can cause chronic thromboembolic pulmonary hypertension, with breathlessness at rest or with mild exertion. Patients with PE are more likely to suffer recurrent VTE than patients with DVT alone.
Genetic and acquired factors contribute to the likelihood of VTE. The two most common autosomal dominant genetic mutations are the factor V Leiden and the prothrombin gene mutations (Chap. 59). However, only a minority of patients with VTE have identifiable predisposing genetic factors. The majority of patients with predisposing genetic factors will not develop clinical evidence of clotting. Acquired predispositions include long-haul air travel, obesity, cigarette smoking, oral contraceptives, pregnancy, postmenopausal hormone replacement, surgery, trauma, and medical conditions such as antiphospholipid antibody syndrome, cancer, systemic arterial hypertension, and chronic obstructive pulmonary disease. Thrombophilia contributes to the risk of venous thrombosis, often due to an inherited risk factor in combination with an acquired predisposition.
Pathophysiology
Embolization
When venous thrombi dislodge from their site of formation, they embolize to the pulmonary arterial circulation or, paradoxically, to the arterial circulation through a patent foramen ovale or atrial septal defect. About half of patients with pelvic vein thrombosis or proximal leg DVT develop PE, which is usually asymptomatic. Isolated calf vein thrombi pose a much lower risk of PE, but they are the most common source of paradoxical embolism. These tiny thrombi can cross a small patent foramen ovale or atrial septal defect, unlike larger, more proximal leg thrombi. With increased use of chronic indwelling central venous catheters for hyperalimentation and chemotherapy, as well as more frequent insertion of permanent pacemakers and internal cardiac defibrillators, upper extremity venous thrombosis is becoming a more common problem. These thrombi rarely embolize and cause PE.
Physiology
The most common gas exchange abnormalities are hypoxemia (decreased arterial PO2) and an increased alveolar-arterial O2 tension gradient, which represents the inefficiency of O2 transfer across the lungs. Anatomic dead space increases because breathed gas does not enter gas exchange units of the lung. Physiologic dead space increases because ventilation to gas exchange units exceeds venous blood flow through the pulmonary capillaries.
Other pathophysiological abnormalities include:
Increased pulmonary vascular resistance due to vascular obstruction or platelet secretion of vasoconstricting neurohumoral agents such as serotonin. Release of vasoactive mediators can produce ventilation-perfusion mismatching at sites remote from the embolus, thereby accounting for a potential discordance between a small PE and a large alveolar-arterial O 2 gradient.
Impaired gas exchange due to increased alveolar dead space from vascular obstruction, hypoxemia from alveolar hypoventilation relative to perfusion in the nonobstructed lung, right-to-left shunting, and impaired carbon monoxide transfer due to loss of gas exchange surface.
Alveolar hyperventilation due to reflex stimulation of irritant receptors
Increased airway resistance due to constriction of airways distal to the bronchi
Decreased pulmonary compliance due to lung edema, lung hemorrhage, or loss of surfactant
Right Ventricular (Rv) Dysfunction
Progressive right heart failure is the usual cause of death from PE. In the International Cooperative Pulmonary Embolism Registry (ICOPER), the presence of RV dysfunction on baseline echocardiography of PE patients who presented with a systolic blood pressure >90 mmHg was associated with a doubling of the 3-month mortality rate. As pulmonary vascular resistance increases, RV wall tension rises and causes further RV dilatation and dysfunction. RV contraction continues even after the left ventricle (LV) starts relaxing at end-systole. Consequently, the interventricular septum bulges into and compresses an intrinsically normal left ventricle. Diastolic LV impairment develops, attributable to septal displacement, and results in reduced LV distensibility and impaired LV filling during diastole. Increased RV wall tension also compresses the right coronary artery, diminishes subendocardial perfusion, limits myocardial oxygen supply, and may precipitate myocardial ischemia and RV infarction. Underfilling of the LV may lead to a fall in left ventricular cardiac output and systemic arterial pressure, thereby provoking myocardial ischemia due to compromised coronary artery perfusion. Eventually, circulatory collapse and death may ensue.
Diagnosis
Clinical Evaluation
The diagnosis is challenging because symptoms and signs are nonspecific. VTE mimics other illnesses, and PE is known as "The Great Masquerader."
For patients who have DVT, the most frequent history is a cramp in the lower calf that persists for several days and that becomes more uncomfortable as time progresses. For patients who have PE, the most frequent history is unexplained breathlessness.
When evaluating patients with possible DVT, the initial task is to decide whether the clinical likelihood for DVT is low. When evaluating possible PE, the initial task is to decide whether the clinical likelihood is high. Patients with low likelihood of DVT or non-high (i.e., low/moderate) likelihood of PE can undergo initial diagnostic evaluation with D-dimer testing alone (see below) without obligatory imaging tests (Fig. 256-1).
Figure 256-1
How to decide whether diagnostic imaging is needed. For assessment of clinical likelihood, see Table 256-1.
Point score methods are useful for estimating the clinical likelihood of DVT and PE (Table 256-1).
Table 256-1 Clinical Decision Rules
Low Clinical Likelihood of DVT If the Point Score Is Zero or Less
Clinical Variable
Score
Active cancer 1
Paralysis, paresis, or recent cast 1
Bedridden for >3 days; major surgery <12 weeks 1
Tenderness along distribution of deep veins 1
Entire leg swelling 1
Unilateral calf swelling >3 cm 1
Pitting edema 1
Collateral superficial nonvaricose veins 1
Alternative diagnosis at least as likely as DVT –2
High Clinical Likelihood of PE if the Point Score Exceeds 4
Clinical Variable
Score
Signs and symptoms of DVT 3.0
Alternative diagnosis less likely than PE 3.0
Heart rate >100/min 1.5
Immobilization >3 days; surgery within 4 weeks 1.5
Prior PE or DVT 1.5
Hemoptysis 1.0
Cancer 1.0
Clinical Syndromes
The differential diagnosis is critical because not all leg pain is due to DVT and not all dyspnea is due to PE (Table 256-2). Sudden, severe calf discomfort suggests a ruptured Baker's cyst. Fever and chills usually herald cellulitis rather than DVT, though DVT may be present concomitantly. Physical findings, if present at all, may simply consist of mild palpation discomfort in the lower calf. Massive DVT is much easier to recognize. The patient presents with severe thigh swelling and marked tenderness when palpating the inguinal area and common femoral vein. In extreme cases, patients will be unable to walk or may require a cane, crutches, or walker.
Table 256-2 Differential Diagnosis
DVT
Ruptured Baker's cyst
Cellulitis
Postphlebitic syndrome/venous insufficiency
PE
Pneumonia, asthma, chronic obstructive pulmonary disease
Congestive heart failure
Pericarditis
Pleurisy: "viral syndrome," costochondritis, musculoskeletal discomfort
Rib fracture, pneumothorax
Acute coronary syndrome
Anxiety
If the leg is diffusely edematous, DVT is unlikely. Much more common is an acute exacerbation of venous insufficiency due to postphlebitic syndrome. Upper extremity venous thrombosis may present with asymmetry in the supraclavicular fossa or in the circumference of the upper arms. A prominent superficial venous pattern may be evident on the anterior chest wall.
Patients with massive PE present with systemic arterial hypotension and usually have anatomically widespread thromboembolism. Those with moderate to large PE have RV hypokinesis on echocardiography but normal systemic arterial pressure. Patients with small to moderate PE have both normal right heart function and normal systemic arterial pressure. They have an excellent prognosis with adequate anticoagulation.
The presence of pulmonary infarction usually indicates a small PE, but one that is exquisitely painful, because it lodges peripherally, near the innervation of pleural nerves. Pleuritic chest pain is more common with small, peripheral emboli. However, larger, more central PEs can occur concomitantly with peripheral pulmonary infarction.
Nonthrombotic PE may be easily overlooked. Possible etiologies include fat embolism after blunt trauma and long bone fractures, tumor embolism, bone marrow, or air embolism. Cement embolism and bony fragment embolism can occur after total hip or knee replacement. Intravenous drug users may inject themselves with a wide array of substances, such as hair, talc, or cotton. Amniotic fluid embolism occurs when fetal membranes leak or tear at the placental margin. Pulmonary edema in this syndrome is probably due to alveolar capillary leakage.
Dyspnea is the most frequent symptom of PE, and tachypnea is its most frequent sign. Whereas dyspnea, syncope, hypotension, or cyanosis indicates a massive PE, pleuritic pain, cough, or hemoptysis often suggests a small embolism located distally near the pleura. On physical examination, young and previously healthy individuals may appear anxious but otherwise seem deceptively well, even with an anatomically large PE. They may only have dyspnea with moderate exertion. They often lack "classic" signs such as tachycardia, low-grade fever, neck vein distension, or an accentuated pulmonic component of the second heart sound. Sometimes paradoxical bradycardia occurs.
Some patients have occult PE and an overt coexisting illness such as pneumonia or heart failure. In such circumstances, clinical improvement often fails to occur despite standard medical treatment of the concomitant illness. This situation can serve as a clinical clue to the possible coexistence of PE.
Nonimaging Diagnostic Modalities
Nonimaging tests are best utilized in combination with clinical likelihood of DVT or PE (Fig. 256-1).
Blood Tests
The quantitative plasma D-dimerenzyme-linked immunosorbent assay (ELISA) rises in the presence of DVT or PE because of plasmin's breakdown of fibrin. Elevation of D-dimer indicates endogenous although often clinically ineffective thrombolysis. The sensitivity of the D-dimer is greater than 80% for DVT (including isolated calf DVT) and greater than 95% for PE. The D-dimer is less sensitive for DVT than PE because the DVT thrombus size is smaller. The D-dimer is a useful "rule out" test. It is normal (<500 ng/mL) in more than 95% of patients without PE. In patients with low clinical suspicion of DVT, it is normal in more than 90% without DVT.
The D-dimer assay is not specific. Levels increase in patients with myocardial infarction, pneumonia, sepsis, cancer, the postoperative state, and second or third trimester of pregnancy. Therefore, it rarely has a useful role among hospitalized patients because their D-dimers are frequently elevated due to some systemic illness.
Contrary to classic teaching, arterial blood gases lack diagnostic utility for PE, even though both the PO2 and PCO2 often decrease. Among patients suspected of PE, neither the room air arterial PO2 nor calculation of the alveolar-arterial O2 gradient can reliably differentiate or triage patients who actually have PE at angiography.
Elevated Cardiac Biomarkers
Serum troponin levels increase in RV microinfarction. Myocardial stretch often results in elevation of brain natriuretic peptide or NT-pro-brain natriuretic peptide. Elevated cardiac biomarkers predict an increase in major complications and mortality from PE.
Electrocardiogram
The most cited abnormality, in addition to sinus tachycardia, is the S1Q3T3 sign: an S wave in lead I, Q wave in lead III, and inverted T wave in lead III (Chap. 221). This finding is relatively specific but insensitive. Perhaps the most frequent abnormality is T-wave inversion in leads V1 to V4.
Noninvasive Imaging Modalities
Venous Ultrasonography
Ultrasonography of the deep venous system (Table 256-3) relies upon loss of vein compressibility as the primary criterion for DVT. When a normal vein is imaged in cross-section, it readily collapses with gentle manual pressure from the ultrasound transducer. This creates the illusion of a "wink." With acute DVT, the vein loses its compressibility because of passive distension by acute thrombus. The diagnosis of acute DVT is even more secure when thrombus is directly visualized. It appears homogeneous and has low echogenicity (Fig. 256-2). The vein itself often appears mildly dilated, and collateral channels may be absent.
Table 256-3 Ultrasonography of the Deep Leg Veins
Criteria for Establishing the Diagnosis of Acute DVT
Lack of vein compressibility (the principal criterion)
Vein does not "wink" when gently compressed in cross-section
Failure to appose the walls of the vein due to passive distension
Direct Visualization of Thrombus
Homogenous
Low echogenicity
Abnormal Doppler Flow Dynamics
Normal response: calf compression augments Doppler flow signal and confirms vein patency proximal and distal to Doppler
Abnormal response: flow blunted rather than augmented with calf compression
Figure 256-2
Acute DVT on venous ultrasound examination. The vein is not compressible and thrombus (far left arrow) is visualized directly in the deep venous system. SFV, superficial femoral vein (which is a deep vein, despite the terminology "superficial"); DFV, deep femoral vein (synonymous with profunda femoral vein). (From the personal collection of Samuel Z. Goldhaber, MD; with permission.)
Venous flow dynamics can be examined with Doppler imaging. Normally, manual calf compression causes augmentation of the Doppler flow pattern. Loss of normal respiratory variation is caused by obstructing DVT or by any obstructive process within the pelvis. Because DVT and PE are so closely related and are both treated with anticoagulation (see below), confirmed DVT is usually an adequate surrogate for PE. In contrast, a normal venous ultrasound does not exclude PE. The majority of patients with PE have no imaging evidence of DVT, probably because the clot has already embolized to the lung or is in the pelvic veins, where ultrasonography is usually inadequate. In patients without DVT, the ultrasound examination may identify other reasons for leg discomfort such as a Baker's cyst (also known as a popliteal or synovial cyst) or a hematoma. For patients with a technically poor or nondiagnostic venous ultrasound, consider alternative imaging modalities for DVT such as CT or magnetic resonance imaging.
Chest Roentgenography
A normal or near-normal chest x-ray in a dyspneic patient often occurs in PE. Well-established abnormalities include focal oligemia (Westermark's sign), a peripheral wedged-shaped density above the diaphragm (Hampton's hump), or an enlarged right descending pulmonary artery (Palla's sign).
Chest CT
Computed tomography (CT) of the chest with intravenous contrast is the principal imaging test for the diagnosis of PE (Fig. 256-3). Multidetector-row spiral CT acquires all chest images with 1 mm resolution during a short breath hold. This generation of CT scanners can image small peripheral emboli. Sixth-order branches can be visualized with resolution superior to conventional invasive contrast pulmonary angiography. The CT scan also obtains excellent images of the RV and LV and can be used for a risk stratification as well as a diagnostic tool. In patients with PE, RV enlargement on chest CT indicates a fivefold increased likelihood of death within the next 30 days compared with PE patients with normal RV size on chest CT. When imaging is continued below the chest to the knee, pelvic and proximal leg DVT can also be diagnosed by CT scanning. In patients without PE, the lung parenchymal images may establish alternative diagnoses not apparent on chest x-ray that explain the presenting symptoms and signs, such as pneumonia, emphysema, pulmonary fibrosis, pulmonary mass, or aortic pathology. Sometimes asymptomatic early stage lung cancer is diagnosed incidentally.
Figure 256-3
Large bilateral proximal PE on chest CT following radical prostatectomy.
Lung Scanning
Lung scanning is now a second-line diagnostic test for PE. It is mostly used for patients who cannot tolerate intravenous contrast. Small particulate aggregates of albumin labeled with a gamma-emitting radionuclide are injected intravenously and are trapped in the pulmonary capillary bed. The perfusion scan defect indicates absent or decreased blood flow, possibly due to PE. Ventilation scans, obtained with radiolabeled inhaled gases such as xenon or krypton, improve the specificity of the perfusion scan. Abnormal ventilation scans indicate abnormal nonventilated lung, thereby providing possible explanations for perfusion defects other than acute PE, such as asthma or chronic obstructive pulmonary disease. A high probability scan for PE is defined as having two or more segmental perfusion defects in the presence of normal ventilation.
The diagnosis of PE is very unlikely in patients with normal and near-normal scans but is about 90% certain in patients with high-probability scans. Unfortunately, most patients have nondiagnostic scans, and fewer than half of patients with angiographically confirmed PE have a high-probability scan. As many as 40% of patients with high clinical suspicion for PE and "low-probability" scans do, in fact, have PE at angiography.
Magnetic Resonance (MR) (Contrast-Enhanced)
When ultrasound is equivocal, MR venography is an excellent imaging modality to diagnose DVT. MR utilizes gadolinium contrast agent, which, unlike iodinated contrast agents used in venography or CT angiography, is not nephrotoxic. MR imaging should be considered for suspected DVT or PE patients with renal insufficiency or contrast dye allergy. MR pulmonary angiography detects large proximal PE but is not reliable for smaller segmental and subsegmental PE.
Echocardiography
Echocardiography is not a reliable diagnostic imaging tool for acute PE because most patients with PE have normal echocardiograms. However, echocardiography is a very useful diagnostic tool for detecting conditions that might mimic PE, such as acute myocardial infarction, pericardial tamponade, or aortic dissection.
Transthoracic echocardiography rarely images thrombus directly. The best-known indirect sign of PE on transthoracic echocardiography is McConnell's sign, hypokinesis of the RV free wall with normal motion of the RV apex.
Transesophageal echocardiography should be considered when CT scanning facilities are not available or when a patient has renal failure or severe contrast allergy that precludes administration of contrast despite premedication with high dose steroids. This imaging modality can directly visualize large proximal PE.
Invasive Diagnostic Modalities
Pulmonary Angiography
Chest CT with contrast (see above) has virtually replaced invasive pulmonary angiography as a diagnostic test. Invasive catheter-based diagnostic testing is reserved for patients with technically unsatisfactory chest CTs or for those in whom an interventional procedure such as catheter-directed thrombolysis or embolectomy is planned. A definitive diagnosis of PE depends upon visualization of an intraluminal filling defect in more than one projection. Secondary signs of PE include abrupt occlusion ("cut-off") of vessels, segmental oligemia or avascularity, a prolonged arterial phase with slow filling, or tortuous, tapering peripheral vessels.
Contrast Phlebography
Venous ultrasonography has virtually replaced contrast phlebography as the diagnostic test for suspected DVT.
Integrated Diagnostic Approach
An integrated diagnostic approach (Fig. 256-1) streamlines the workup of suspected DVT and PE (Fig. 256-4).
Figure 256-4
Imaging tests to diagnose DVT and PE.
Deep Venous Thrombosis: Treatment
Primary Therapy versus Secondary Prevention
Primary therapy consists of clot dissolution with thrombolysis or removal of PE by embolectomy. Anticoagulation with heparin and warfarin or placement of an inferior vena caval filter constitutes secondary prevention of recurrent PE rather than primary therapy.
Risk Stratification
Rapid and accurate risk stratification is critical in determining optimal treatment strategy. The presence of hemodynamic instability, RV dysfunction, or elevation of the troponin level due to RV microinfarction can identify high-risk patients. Detection of RV hypokinesis on echocardiography is the most widely used approach to risk stratification. However, RV enlargement on chest CT also predicts an increased mortality rate from PE. The combination of RV dysfunction plus elevated biomarkers such as troponin portends an especially ominous prognosis.
Primary therapy should be reserved for patients at high risk of an adverse clinical outcome. When RV function remains normal in a hemodynamically stable patient, a good clinical outcome is highly likely with anticoagulation alone (Fig. 256-5).
Figure 256-5
Acute management of pulmonary thromboembolism. RV, right ventricular; IVC, inferior vena cava.
Massive Pulmonary Embolism: Treatment
Anticoagulation
Anticoagulation is the foundation for successful treatment of DVT and PE (Table 256-4). Immediately effective anticoagulation is initiated with a parenteral drug: unfractionated heparin (UFH), low molecular weight heparin (LMWH), or fondaparinux. These parenteral drugs (see below) are continued as a transition or "bridge" to stable, long-term anticoagulation with a vitamin K antagonist (exclusively warfarin in the United States). The first dose of warfarin may be given as soon as several hours after the bridging anticoagulant if LMWH or fondaparinux are used. Otherwise, with UFH a therapeutic aPTT must first be documented. Warfarin requires 5–7 days to achieve a therapeutic effect. During that period, the parenteral and oral agents are overlapped. After 5–7 days of anticoagulation, residual thrombus begins to become endothelialized in the vein or pulmonary artery. However, anticoagulants do not directly dissolve thrombus that already exists.
Table 256-4 Anticoagulation of VTE
Immediate Parenteral Anticoagulation
Unfractionated heparin, bolus and continuous infusion, to achieve aPTT 2–3 times the upper limit of the laboratory normal, or
Enoxaparin 1 mg/kg twice daily with normal renal function, or
Tinzaparin 175 units/kg once daily with normal renal function, or
Fondaparinux weight based once daily; adjust for impaired renal function
Warfarin Anticoagulation
Usual start dose is 5–10 mg.
Titrate to INR, target 2.0–3.0.
Continue parenteral anticoagulation for a minimum of 5 days and until 2 sequential INR values, at least 1 day apart, return in the target range.
Unfractionated Heparin
Unfractionated heparin (UFH) anticoagulates by binding to and accelerating the activity of antithrombin III, thus preventing additional thrombus formation and permitting endogenous fibrinolytic mechanisms to lyse clot that has already formed. UFH is dosed to achieve a target activated partial thromboplastin time (aPTT) that is 2–3 times the upper limit of the laboratory normal. This is usually equivalent to an aPTT of 60–80 s. For UFH, a typical intravenous bolus is 5000–10,000 units followed by a continuous infusion of 1000–1500 units/h. Nomograms based upon a patient's weight may assist in adjusting the dose of heparin. The most popular nomogram utilizes an initial bolus of 80 units/kg, followed by an initial infusion rate of 18 units/kg per hour.
The major advantage of UFH is that it has a short half-life. Its anticoagulant effect abates after several hours. This is especially useful if the patient will undergo an invasive procedure such as surgical embolectomy.
The major disadvantage of UFH is that achieving the target aPTT can be difficult and may require repeated blood sampling and heparin dose adjustment every 4–6 h. Furthermore, by using UFH, patients are at risk of developing heparin-induced thrombocytopenia.
Low Molecular Weight Heparins
These fragments of UFH exhibit less binding to plasma proteins and endothelial cells and consequently have greater bioavailability, a more predictable dose response, and a longer half-life than UFH. No monitoring or dose adjustment is needed unless the patient is markedly obese or has renal insufficiency.
Enoxaparin 1 mg/kg twice daily and tinzaparin 175 units/kg once daily have received U.S. Food and Drug Administration (FDA) approval for treatment of patients who present with DVT. The weight-adjusted doses must be adjusted downward in renal insufficiency because the kidneys excrete LMWH.
Fondaparinux
Fondaparinux, an anti-Xa pentasaccharide, is administered by once-daily subcutaneous injection and has been approved by the FDA to treat DVT and PE. No laboratory monitoring is required. Patients weighing <50 kg receive 5 mg, 50–100 kg patients receive 7.5 mg, and patients weighing >100 kg receive 10 mg. The dose must be adjusted downward for patients with renal dysfunction because the drug is excreted by the kidneys.
Warfarin
This vitamin K antagonist prevents carboxylation activation of coagulation factors II, VII, IX, and X. The full effect of warfarin requires at least 5 days, even if the prothrombin time, used for monitoring, becomes elevated more rapidly. If warfarin is initiated as monotherapy during an acute thrombotic illness, a paradoxical exacerbation of hypercoagulability can increase the likelihood of thrombosis rather than prevent it. Overlapping UFH, LMWH, or fondaparinux with warfarin for at least 5 days can counteract the early procoagulant effect of unopposed warfarin.
Dosing
In an average-sized adult, warfarin is usually initiated in a dose of 5 mg. Doses of 7.5 or 10 mg can be used in obese or large-framed young patients who are otherwise healthy. Patients who are malnourished or who have received prolonged courses of antibiotics are probably deficient in vitamin K and should receive smaller initial doses of warfarin, such as 2.5 mg. The prothrombin time is standardized with the INR, which assesses the anticoagulant effect of warfarin (Chap. 59). The target INR is usually 2.5, with a range of 2.0–3.0.
The warfarin dose is titrated to achieve the target INR. Proper dosing is difficult because hundreds of drug-drug and drug-food interactions affect warfarin metabolism. Furthermore, variables such as increasing age and comorbidities such as systemic illness, malabsorption, and diarrhea reduce the warfarin-dosing requirement.
No reliable nomogram has been established to predict how individual patients will respond to warfarin. Therefore, dosing is adjusted according to an "educated guess." Centralized anticoagulation clinics have improved the efficacy and safety of warfarin dosing. Based upon a meta-analysis of trials comparing anticoagulation clinic care versus self-monitoring, patients benefit if they can self-monitor their INR with a home point-of-care fingerstick machine. The subgroup with the best results also learns to self-adjust warfarin doses.
Pharmacogenomics may provide the gateway to rational dosing of warfarin. A recent discovery is that five polymorphisms of the vitamin K receptor gene explain 25% of the variance in warfarin dosing. These polymorphisms can stratify patients into low, intermediate, and high-dose warfarin groups. An additional 10% of dosing variance can be explained by allelic variants of the cytochrome P-450 enzyme 2C9. These mutations decrease warfarin dosing because they impair the metabolism of the S-enantiomer of warfarin. In the future, if rapid turnaround of genetic testing becomes possible, warfarin could be dosed according to specific pharmacogenomic profiles.
Complications of Anticoagulants
The most important adverse effect of anticoagulation is hemorrhage. For life-threatening or intracranial hemorrhage due to heparin or LMWH, protamine sulfate can be administered. There is no specific antidote for bleeding from fondaparinux.
Major bleeding from warfarin is traditionally managed with cryoprecipitate or fresh-frozen plasma (usually 2–4 units) to achieve rapid hemostasis. Recombinant human coagulation factor VIIa (rFVIIa), FDA-approved for bleeding in hemophiliacs, is widely used off-label to manage catastrophic bleeding from warfarin. The optimal dose appears to be 40 mcg/kg. The greatest risk of this therapy is rebound thromboembolism. For minor bleeding, or to manage an excessively high INR in the absence of bleeding, a small 2.5 mg dose of oral vitamin K may be administered.
Heparin-induced thrombocytopenia (HIT) and osteopenia are far less common with LMWH than with UFH. Thrombosis due to HIT should be managed with a direct thrombin inhibitor: argatroban for patients with renal insufficiency or lepirudin for patients with hepatic failure. In the setting of percutaneous coronary intervention, administer bivalirudin.
The most common nonbleeding side effect of warfarin is alopecia. A rare complication is warfarin-induced skin necrosis, which may be related to warfarin-induced reduction of protein C.
During pregnancy, warfarin should be avoided if possible because of warfarin embryopathy, which is most common with exposure during the 6th through 12th week of gestation. However, women can take warfarin postpartum and breast-feed safely. Warfarin can also be administered safely during the second trimester.
Duration of Hospital Stay
Acute DVT patients with good family and social support, permanent residence, telephone, and no hearing or language impairment can often be managed as outpatients. They or a family member or a visiting nurse can administer a parenteral anticoagulant. Warfarin dosing can be titrated to the INR and adjusted on an outpatient basis.
Acute PE patients, who traditionally have required 5-7 day hospital stays for intravenous heparin as a "bridge" to warfarin, can be considered for abbreviated hospitalization if they have an excellent prognosis. The latter are characterized by clinical stability, absence of chest pain or shortness of breath, normal right ventricular size and function, and normal levels of cardiac biomarkers.
Duration of Anticoagulation
Patients with PE following surgery or trauma ordinarily have a low rate of recurrence after 3–6 months of anticoagulation. For DVT isolated to an upper extremity or calf that has been provoked by surgery or trauma, 3 months of anticoagulation suffices. For provoked proximal leg DVT or PE, 6 months of anticoagulation is sufficient.
However, among patients with "idiopathic," unprovoked DVT or PE, the recurrence rate is surprisingly high after cessation of anticoagulation. VTE that occurs during long-haul air travel is considered unprovoked.
Current American College of Chest Physicians (ACCP) guidelines recommend anticoagulation for an indefinite duration with a target INR between 2.0 and 3.0 for patients with idiopathic VTE. However, I recommend that the intensity of anticoagulation be tailored to the patient's risk of recurrent VTE versus risk of bleeding. For a patient at high risk of recurrent VTE (for example, someone with multiple thrombophilic disorders) and a low risk of bleeding (for example, young age and no comorbidities), I recommend standard intensity anticoagulation. However, for a patient with a high bleeding risk (for example, older age and a prior history of gastrointestinal bleeding), I advise low-intensity anticoagulation (INR 1.5–2.0) after 6 months.
Several years ago, the presence of genetic mutations such as factor V Leiden or prothrombin gene mutation was thought to markedly increase the risk of recurrent VTE. Now, however, the clinical circumstances in which the DVT or PE occurs rather than underlying thrombophilia are considered much more important in deciding the risk of recurrence and the optimal duration of anticoagulation. However, patients with moderate or high levels of anticardiolipin antibodies probably warrant indefinite duration anticoagulation, even if the initial VTE was provoked by trauma or surgery.
Inferior Vena Caval (IVC) Filters
The two principal indications for insertion of an IVC filter are (1) active bleeding that precludes anticoagulation, and (2) recurrent venous thrombosis despite intensive anticoagulation. Prevention of recurrent PE in patients with right heart failure who are not candidates for fibrinolysis or prophylaxis of extremely high-risk patients are "softer" indications for filter placement. The filter itself may fail by permitting the passage of small to medium-sized clots. Large thrombi may embolize to the pulmonary arteries via collateral veins that develop. A more common complication is caval thrombosis with marked bilateral leg swelling.
Paradoxically, by providing a nidus for clot formation, filters double the DVT rate over the ensuing 2 years following placement. Therefore, if clinically safe, patients receiving IVC filters should also receive concomitant anticoagulation.
Retrievable filters can now be placed for patients with an anticipated temporary bleeding disorder or for patients at temporary high risk of PE, such as individuals undergoing bariatric surgery with a prior history of perioperative PE. The filters can be retrieved up to several months following insertion, unless thrombus forms and is trapped within the filter. The retrievable filter becomes permanent if it remains in place or if, for technical reasons such as rapid endothelialization, it cannot be removed.
Maintaining Adequate Circulation
For patients with massive PE and hypotension, the most common initial approach is administration of 500–1,000 ml of normal saline. However, fluids should be used with extreme caution. Excessive fluid administration exacerbates RV wall stress, causes more profound RV ischemia, and worsens LV compliance and filling by causing further interventricular septal shift toward the LV. Dopamine and dobutamine are first-line inotropic agents for treatment of PE-related shock. There should be a low threshold to initiate these pressors. However, a "trial and error" approach may be necessary with other agents such as norepinephrine, vasopressin, or phenylephrine.
Fibrinolysis
Successful fibrinolytic therapy rapidly reverses right heart failure and leads to a lower rate of death and recurrent PE. Thrombolysis usually (1) dissolves much of the anatomically obstructing pulmonary arterial thrombus; (2) prevents the continued release of serotonin and other neurohumoral factors that exacerbate pulmonary hypertension; and (3) dissolves much of the source of the thrombus in the pelvic or deep leg veins, thereby decreasing the likelihood of recurrent PE.
The preferred fibrinolytic regimen is 100 mg of recombinant tissue plasminogen activator (tPA) administered as a continuous peripheral intravenous infusion over 2 h. Patients appear to respond to fibrinolysis for up to 14 days after the PE has occurred.
Contraindications to fibrinolysis include intracranial disease, recent surgery, or trauma. The overall major bleeding rate is about 10%, including a 1–3% risk of intracranial hemorrhage. Careful screening of patients for contraindications to fibrinolytic therapy (Chap. 239) is the best way to minimize bleeding risk.
The only FDA-approved indication for PE fibrinolysis is massive PE. For patients with preserved systolic blood pressure and submassive PE, guidelines recommend individual patient risk assessment of the thrombotic burden versus bleeding risk. I concur with these guidelines. Younger patients with submassive PE but without comorbidities are generally excellent candidates for fibrinolysis. For older patients (>70 yrs) with risk of intracranial hemorrhage, a "watch and wait" approach is suitable, with frequent serial evaluation of RV function by echocardiography; fibrinolysis should be considered in those with deterioration of RV function.
Pulmonary Embolectomy
The risk of intracranial hemorrhage with fibrinolysis has prompted the renaissance of surgical embolectomy for acute PE. At Brigham and Women's Hospital, 47 patients with massive PE underwent emergency surgery in 53 months, with a 94% survival rate. This high survival rate may be attributed to improved surgical technique, rapid diagnosis and triage, and careful patient selection. A possible alternative to open surgical embolectomy is catheter embolectomy. New generation catheters are under development.
Pulmonary Thromboendarterectomy
Chronic thromboembolic pulmonary hypertension is caused by vascular obstruction at the capillary level, not direct thromboembolic occlusion. It used to be considered a rare complication (about 1 of 500) of acute PE. Now, however, it appears that chronic thromboembolic pulmonary hypertension is a more common development, occurring in approximately 4% of patients who develop acute PE. Therefore, PE patients should be followed to ensure that if they have initial pulmonary hypertension, it abates over time (usually 6 weeks).
Patients severely impaired with dyspnea due to chronic thromboembolic pulmonary hypertension should be considered for pulmonary thromboendarterectomy, which, if successful, can markedly reduce and at times even cure pulmonary hypertension (Chap. 244). The operation requires median sternotomy, cardiopulmonary bypass, deep hypothermia, and periods of hypothermic circulatory arrest. The fibrotic, thromboembolic material is grasped with a forceps and circumferentially dissected from the vessel wall. The mortality rate at experienced centers is approximately 5%. The two most common complications are (1) "pulmonary steal," where blood rushes from previously perfused areas to newly revascularized areas of the lung; and (2) reperfusion pulmonary edema.
Emotional Support
Many patients with VTE will appear healthy and fit. They may be burdened with fear about the possible genetic implications of DVT or PE. They often feel overwhelmed when advised to continue lifelong anticoagulation. Many patients in whom anticoagulation is discontinued after 3–6 months of therapy feel vulnerable to a future recurrent VTE. They may be reluctant to discontinue warfarin. Support groups are useful. Responses to frequently asked questions by these patients have been posted on the following website: http://web.mit.edu/karen/www/faq.html.
Prevention of Postphlebitic Syndrome
The only therapy to prevent postphlebitic syndrome is daily use of below-knee 30–40 mmHg vascular compression stockings. They halve the rate of developing postphlebitic syndrome. These vascular compression stockings should be prescribed as soon as DVT is diagnosed, and the stockings should be fitted carefully to maximize their benefit. When patients are in bed, the stockings need not be worn.
Prevention of VTE
Prophylaxis is of paramount importance because VTE is difficult to detect and poses an excessive medical and economic burden. Mechanical and pharmacologic measures often succeed in preventing this complication (Table 256-5). Patients at high risk can receive a combination of mechanical and pharmacologic modalities. Graduated compression stockings and pneumatic compression devices may complement mini-dose unfractionated heparin (5000 units subcutaneously twice or preferably three times daily), low molecular weight heparin, a pentasaccharide (fondaparinux 2.5 mg daily), or warfarin administration. Computerized reminder systems can increase the use of preventive measures and at Brigham and Women's Hospital reduced the symptomatic VTE rate by more than 40%. Patients who have undergone total hip replacement, total knee replacement, or cancer surgery will benefit from extended pharmacologic prophylaxis for a total of 4–6 weeks.
Table 256-5 Prevention of Venous Thromboembolism
Condition Prophylaxis Strategy
High-risk general surgery Mini-UFH + GCS or LMWH + GCS
Thoracic surgery Mini-UFH + IPC
Cancer surgery, including gynecologic cancer surgery LMWH, consider 1 month of prophylaxis
Total hip replacement, total knee replacement, hip fracture surgery LMWH, fondaparinux (a pentasaccharide) 2.5 mg sc, once daily or (except for total knee replacement) warfarin (target INR 2.5)
Neurosurgery GCS + IPC
Neurosurgery for brain tumor Mini-UFH or LMWH, + IPC, + predischarge venous ultrasonography
Benign gynecologic surgery Mini-UFH + GCS
Medically ill patients Mini-UFH or LMWH
Anticoagulation contraindicated GCS + IPC
Long-haul air travel Consider LMWH for very high risk patients
Note: Mini-UFH, minidose unfractionated heparin, 5000 units subcutaneously twice (less effective) or three times daily (more effective); GCS, graduated compression stockings, usually 10–18 mm Hg; LMWH, low-molecular-weight heparin, typically in the United States, enoxaparin, 40 mg once daily, or dalteparin, 2500 or 5000 units once daily; IPC, intermittent pneumatic compression devices.
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