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Deep Venous Thrombosis and Pulmonary Thromboembolism: Introduction Epidemiology Venous thromboembolism (VTE), which encompasses deep venous thrombosis (DVT) and pulmonary embolism (PE), is one of the three major cardiovascular causes of death, along with myocardial infarction and stroke. VTE can cause death from PE or, among survivors, chronic thromboembolic pulmonary hypertension and postphlebitic syndrome. The U.S. Surgeon General has declared that PE is the most common preventable cause of death among hospitalized patients. Medicare has labeled PE and DVT occurring after total hip or knee replacement as unacceptable “never events” and no longer reimburses hospitals for the incremental expenses associated with treating this postoperative complication. New nonprofit organizations have begun educating health care professionals and the public on the medical consequences of VTE, along with risk factors and warning signs. Between 100,000 and 300,000 VTE-related deaths occur annually in the United States. Mortality rates and length of hospital stay are decreasing as charges for hospital care increase. Approximately three of four symptomatic VTE events occur in the community, and the remainder are hospital acquired. Approximately 14 million (M) hospitalized patients are at moderate to high risk for VTE in the United States annually: 6 M major surgery patients and 8 M medical patients with comorbidities such as heart failure, cancer, and stroke. The prophylaxis paradigm has changed from voluntary to mandatory compliance with guidelines to prevent VTE among hospitalized patients. With an estimated 370,000 PE-related deaths annually in Europe, the projected direct cost for VTE-associated care exceeds 3 billion euros per year. In Japan, as the lifestyle becomes more westernized, the rate of VTE appears to be increasing. The long-term effects of nonfatal VTE lower the quality of life. Chronic thromboembolic pulmonary hypertension is often disabling and causes breathlessness. A late effect of DVT is postphlebitic syndrome, which eventually occurs in more than one-half of DVT patients. Postphlebitic syndrome (also known as postthrombotic syndrome or chronic venous insufficiency) is a delayed complication of DVT that causes the venous valves of the leg to become incompetent and exude interstitial fluid. Patients complain of chronic ankle or calf swelling and leg aching, especially after prolonged standing. In its most severe form, postphlebitic syndrome causes skin ulceration, especially in the medial malleolus of the leg. There is no effective medical therapy for this condition. Prothrombotic States Thrombophilia contributes to the risk of venous thrombosis. The two most common autosomal dominant genetic mutations are factor V Leiden, which causes resistance to activated protein C (which inactivates clotting factors V and VIII), and the prothrombin gene mutation, which increases the plasma prothrombin concentration. Antithrombin, protein C, and protein S are naturally occurring coagulation inhibitors. Deficiencies of these inhibitors are associated with VTE but are rare. Hyperhomocysteinemia can increase the risk of VTE, but lowering the homocysteine level with folate, vitamin B6, or vitamin B12 does not reduce the incidence of VTE. Antiphospholipid antibody syndrome is the most common acquired cause of thrombophilia and is associated with venous or arterial thrombosis. Other common predisposing factors include cancer, systemic arterial hypertension, chronic obstructive pulmonary disease, long-haul air travel, air pollution, obesity, cigarette smoking, eating large amounts of red meat, oral contraceptives, pregnancy, postmenopausal hormone replacement, surgery, and trauma. Pathophysiology Embolization When venous thrombi are dislodged 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 one-half of patients with pelvic vein thrombosis or proximal leg DVT develop PE, which is often asymptomatic. Isolated calf vein thrombi pose a much lower risk of PE but are the most common source of paradoxical embolism. These tiny thrombi can traverse a 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 pathophysiologic abnormalities include the following: 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 O2 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. As pulmonary vascular resistance increases, RV wall tension rises and causes further RV dilation 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 VTE mimics other illnesses, and PE is known as “the Great Masquerader,” making diagnosis difficult. Occult PE is especially hard to detect when it occurs concomitantly with overt heart failure or pneumonia. In such circumstances, clinical improvement often fails to occur despite standard medical treatment of the concomitant illness. This scenario is a clinical clue to the possible coexistence of PE. For patients who have DVT, the most common history is a cramp in the lower calf that persists for several days and becomes more uncomfortable as time progresses. For patients who have PE, the most common history is unexplained breathlessness. In evaluating patients with possible VTE, the initial task is to decide on the clinical likelihood of the disorder. Patients with a low likelihood of DVT or a low-to-moderate likelihood of PE can undergo initial diagnostic evaluation with d-dimer testing alone (see “Blood tests”) without obligatory imaging tests (Fig. L-1). If the d-dimer is abnormally elevated, imaging tests are the next step. Fig. L-1 : How to decide whether diagnostic imaging is needed. For assessment of clinical likelihood, see Table L-1. Point score methods are useful for estimating the clinical likelihood of DVT and PE (Table L-1). Table L-1 Clinical Decision Rules Low Clinical Likelihood of DVT if Point Score Is Zero or Less; Moderate-Likelihood Score Is 1 to 2; High-Likelihood Score Is 3 or Greater 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 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 L-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 consist only of mild palpation discomfort in the lower calf. Massive DVT is much easier to recognize. The patient presents with marked thigh swelling and tenderness during palpation of the common femoral vein. In extreme cases, patients are unable to walk or may require a cane, crutches, or a walker. Table L-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. More probable 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 pelvic or long bone fracture, tumor embolism, bone marrow, and 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 that can embolize such as hair, talc, and cotton. Amniotic fluid embolism occurs when fetal membranes leak or tear at the placental margin. Pulmonary edema in this syndrome probably is due to alveolar capillary leakage. Dyspnea is the most common symptom of PE, and tachypnea is the most common sign. Dyspnea, syncope, hypotension, or cyanosis indicates a massive PE, whereas pleuritic pain, cough, or hemoptysis often suggests a small embolism situated distally near the pleura. On physical examination, young and previously healthy individuals may appear anxious but otherwise seem well, even with an anatomically large PE. They may have dyspnea only with moderate exertion. They often lack “classic” signs such as tachycardia, low-grade fever, neck vein distention, and an accentuated pulmonic component of the second heart sound. Sometimes paradoxical bradycardia occurs. Nonimaging Diagnostic Modalities Nonimaging tests are best utilized in combination with clinical likelihood assessment of DVT or PE (Fig. L-1). Blood Tests The quantitative plasma d-dimer enzyme-linked immunosorbent assay (ELISA) rises in the presence of DVT or PE because of the breakdown of fibrin by plasmin. Elevation of d-dimer indicates endogenous although often clinically ineffective thrombolysis. The sensitivity of the d-dimer is >80% for DVT (including isolated calf DVT) and >95% for PE. The d-dimer is less sensitive for DVT than for PE because the DVT thrombus size is smaller. The d-dimer is a useful “rule out” test. More than 95% of patients with a normal (<500 ngmL) d-dimer do not have PE. The assay is specific. Levels increase in patients with myocardial infarction, pneumonia, sepsis, cancer, and the postoperative state those second or third trimester of pregnancy. Therefore, rarely has a useful role among hospitalized patients, because levels are frequently elevated due to systemic illness. Contrary classic teaching, arterial blood gases lack diagnostic utility for PE, even though both PO2 Pco2 often decrease. Among suspected having neither room air nor calculation alveolar-arterial O2 gradient can reliably differentiate triage who actually PE at angiography. Elevated Cardiac Biomarkers Serum troponin plasma heart-type fatty acid–binding protein RV microinfarction. Myocardial stretch results elevation brain natriuretic peptide NT-pro-brain peptide. Elevated cardiac biomarkers predict an major complications mortality from PE. Electrocardiogram The most cited abnormality, addition sinus tachycardia, S1Q3T3 sign: S wave lead I, Q III, inverted T III . This finding relatively specific but insensitive. Perhaps common abnormality T-wave inversion leads V1 V4. Noninvasive Imaging Modalities Venous Ultrasonography Ultrasonography deep venous system (Table L-3) relies on loss vein compressibility as primary criterion DVT. When normal imaged cross-section, it readily collapses gentle manual pressure ultrasound transducer. creates illusion “wink.” With acute DVT, loses its passive distention by thrombus. diagnosis DVT more secure when thrombus directly visualized. It appears homogeneous low echogenicity (Fig. L-2). itself mildly dilated, collateral channels may be absent. Table L-3 Ultrasonography Deep Leg Veins Criteria Establishing Diagnosis Acute Lack (principal criterion) Vein does “wink” gently compressed cross-section Failure appose walls distention Direct Visualization Thrombus Homogeneous Low echogenicity Abnormal Doppler Flow Dynamics Normal response: calf compression augments flow signal confirms patency proximal distal Doppler Abnormal blunted rather than augmented compression Fig. L-2 : popliteal 56-year-old man receiving chemotherapy lung cancer. Venous dynamics examined imaging. Normally, causes augmentation pattern. Loss respiratory variation caused obstructing any obstructive process within pelvis. Because so closely related treated anticoagulation (see “Treatment Venous Thrombosis”) confirmed usually adequate surrogate In contrast, exclude About one-half no imaging evidence probably clot already embolized pelvic veins, where ultrasonography inadequate. without examination identify other reasons leg discomfort, such Baker’s cyst (also known synovial cyst) hematoma. For technically poor nondiagnostic ultrasound, one should consider alternative modalities computed tomography (CT) magnetic resonance imaging. Chest Roentgenography A nearly chest x-ray occurs Well-established abnormalities include focal oligemia (Westermark’s sign), peripheral wedged-shaped density above diaphragm (Hampton’s hump), enlarged right descending pulmonary artery (Palla’s sign). Chest CT Computed intravenous contrast principal test L-3). Multidetector-row spiral CT acquires all images ≤1 mm resolution during short breath hold. generation scanners image small emboli. Sixth-order branches visualized superior that conventional invasive angiography. scan also obtains excellent LV used risk stratification along use tool. enlargement indicates increased likelihood death next 30 days compared size CT. continued below knee, diagnosed scanning. parenchymal establish diagnoses apparent explain presenting symptoms signs emphysema, fibrosis, mass, aortic pathology. Sometimes asymptomatic early-stage cancer incidentally. Fig. Large bilateral coronal 54-year-old metastases. He had developed sudden onset heaviness shortness while home. There filling defects main segmental arteries bilaterally (white arrows). Only left upper lobe free thrombus. Lung Scanning Lung scanning become second-line mostly cannot tolerate contrast. Small particulate aggregates albumin labeled gamma-emitting radionuclide injected intravenously trapped capillary bed. perfusion defect absent decreased flow, possibly Ventilation scans, obtained radiolabeled inhaled gas xenon krypton, improve specificity scan. Abnormal ventilation scans indicate abnormal nonventilated lung, thereby providing possible explanations asthma chronic disease. A high-probability defined two presence ventilation. The very unlikely about 90% certain scans. Unfortunately, fewer angiographically high probability As many 40% clinical suspicion “low-probability” do, fact, angiography. Magnetic Resonance (MR) (Contrast-Enhanced) When equivocal, MR venography gadolinium modality diagnose considered VTE renal insufficiency dye allergy. angiography detect large reliable smaller subsegmental PE. Echocardiography Echocardiography tool echocardiograms. However, echocardiography detecting conditions mimic pericardial tamponade, dissection. Transthoracic directly. best-known indirect sign transthoracic McConnell’s hypokinesis wall motion apex. One transesophageal facilities available patient failure severe allergy precludes administration despite premedication high-dose steroids. saddle, main, PE. Invasive Diagnostic Modalities Pulmonary Angiography Chest above) virtually replaced test. Invasive catheter-based testing reserved unsatisfactory CTs whom interventional procedure catheter-directed thrombolysis embolectomy planned. definitive depends visualization intraluminal projection. Secondary abrupt occlusion (“cut-off”) vessels, avascularity, prolonged phase slow filling, tortuous, tapering vessels. Contrast Phlebography Venous phlebography DVT. Integrated Approach An integrated approach L-1) streamlines workup L-4). Figure L-4 tests PE. Treatment: Thrombosis Primary Therapy versus Prevention Primary therapy consists dissolution removal embolectomy. Anticoagulation heparin warfarin placement inferior vena caval filter constitutes secondary prevention recurrent therapy. Risk Stratification Rapid accurate critical determining optimal treatment strategy. hemodynamic instability, dysfunction, enlargement, level microinfarction high-risk patients. echocardiography, CT, rate PE. Primary adverse outcome. function remains hemodynamically stable patient, good outcome highly likely alone L-5). Fig. L-5 management thromboembolism. RV, ventricular; IVC, cava. Treatment: Massive Pulmonary Embolism Anticoagulation Anticoagulation foundation successful L-4). Immediately effective initiated parenteral drug: unfractionated (UFH), low-molecular-weight (LMWH), fondaparinux. One direct thrombin inhibitor—argatroban, lepirudin, bivalirudin—in proven heparin-induced thrombocytopenia. Parenteral agents transition “bridge” stable, long-term vitamin K antagonist (exclusively United States). Warfarin requires 5–7 achieve therapeutic effect. During period, overlap oral agents. After anticoagulation, residual begins endothelialize artery. anticoagulants dissolve exists. Table VTE Immediate Unfractionated heparin, bolus continuous infusion, aPTT three times limit laboratory normal, Enoxaparin 1 mg kg twice daily function, Dalteparin 200 U once 100 daily, or Tinzaparin 175 or Fondaparinux weight-based daily; adjust impaired function Warfarin Usual start dose 5 mg Titrate INR, target 2.0–3.0 Continue minimum until sequential INR values, least day apart, range. Unfractionated Heparin Unfractionated anticoagulates binding accelerating activity antithrombin, thus preventing additional formation permitting endogenous fibrinolytic mechanisms lyse formed. UFH dosed activated partial thromboplastin time (aPTT) 2–3 normal. equivalent 60–80 s. UFH, typical 5000–10,000 units followed infusion 1000–1500 h. Nomograms based patient’s weight assist adjusting heparin. popular nomogram utilizes initial 80 kg, 18 per h. The advantage half-life. especially if undergo disadvantage achieving empirical require repeated sampling adjustment every 4–6 hours. Furthermore, developing thrombocytopenia. Low-Molecular-Weight Heparins These fragments exhibit less proteins endothelial cells consequently greater bioavailability, predictable response, longer half-life UFH. No monitoring needed unless markedly obese kidney disease. There commonly LMWH preparations States: enoxaparin dalteparin. approved bridge VTE. monotherapy symptomatic days, 150 months 2–6. These weight-adjusted doses must reduced disease kidneys metabolize LMWH. Fondaparinux Fondaparinux, anti-Xa pentasaccharide, administered once-daily subcutaneous injection prefilled syringe treat warfarin. required. Patients weighing <50 receive mg, 50–100 7.5>100 kg receive 10 mg. Fondaparinux is synthesized in a laboratory and, unlike LMWH or UFH, is not derived from animal products. It does not cause heparin-induced thrombocytopenia. The dose must be adjusted downward for patients with renal dysfunction because the kidneys metabolize the drug. 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. Warfarin Dosing In an average-size adult, warfarin usually is 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 by calculating the international normalized ratio (INR), which assesses the anticoagulant effect of warfarin . 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. Variables such as increasing age and comorbidities such as systemic illness reduce the required warfarin dose. Pharmacogenomics may provide more precise initial dosing of warfarin, especially for patients who require unusually large or small doses. CYP2C9 variant alleles impair the hydroxylation of S-warfarin, thereby lowering the dose requirement. Variants in the gene encoding the vitamin K epoxide reductase complex 1 (VKORC1) can predict whether patients require low, moderate, or high warfarin doses. Nevertheless, more than half of warfarin dosing variability is caused by clinical factors such as age, sex, weight, concomitant drugs, and comorbid illnesses. Nomograms have been developed (www.warfarindosing.org) to help clinicians initiate warfarin dosing based on clinical information and, if available, pharmacogenetic data. However, most practitioners utilize empirical dosing with an “educated guess.” Centralized anticoagulation clinics have improved the efficacy and safety of warfarin dosing. Patients maintain a therapeutic INR more often if they self-monitor their INR with a home point-of-care fingerstick machine rather than obtaining a coagulation laboratory INR. The patient subgroup with the best results self-adjusts warfarin doses as well as self-tests INRs. Novel Anticoagulants Novel oral anticoagulants are administered in a fixed dose, establish effective anticoagulation within hours of administration, require no laboratory coagulation monitoring, and have few of the drug-drug or drug-food interactions that make warfarin so difficult to dose. Rivaroxaban, a factor Xa inhibitor, and dabigatran, a direct thrombin inhibitor, are approved in Canada and Europe for prevention of VTE after total hip and total knee replacement. In a large-scale trial of acute VTE treatment, dabigatran was as effective as warfarin and had less nonmajor bleeding. Because of these drugs’ rapid onset of action and relatively short half-life compared with warfarin, “bridging” with a parenteral anticoagulant is not required. Complications of Anticoagulants The most serious 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 caused by fondaparinux or direct thrombin inhibitors. Major bleeding from warfarin is best managed with prothrombin complex concentrate. With non-life threatening bleeding in a patient who can tolerate large volume, fresh-frozen plasma can be used. Recombinant human coagulation factor VIIa (rFVIIa), FDA-approved for bleeding in hemophiliacs, is an off-label option to manage catastrophic bleeding from warfarin. For minor bleeding or to manage an excessively high INR in the absence of bleeding, 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 and lepirudin for patients with hepatic failure. In the setting of percutaneous coronary intervention, one should administer bivalirudin. During pregnancy, warfarin should be avoided if possible because of warfarin embryopathy, which is most common with exposure during the sixth through twelfth 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 service, and no hearing or language impairment often can be managed as outpatients. They, a family member, or a visiting nurse must 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 hospital stays of 5–7 days for intravenous heparin as a “bridge” to warfarin, can be considered for abbreviated hospitalization if they have a reliable support system at home and an excellent prognosis. Criteria include clinical stability, absence of chest pain or shortness of breath, normal RV size and function, and normal levels of cardiac biomarkers. Duration of Anticoagulation Patients with PE after surgery, trauma, or estrogen exposure (from oral contraceptives, pregnancy, or postmenopausal therapy) 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, trauma, estrogen, or an indwelling central venous catheter or pacemaker, 3 months of anticoagulation suffices. For provoked proximal leg DVT or PE, 3 to 6 months of anticoagulation is sufficient. For patients with cancer and VTE, the consensus is to prescribe 3–6 months of LMWH as monotherapy without warfarin and to continue anticoagulation indefinitely unless the patient is rendered cancer-free. However, there is uncertainty whether subsequent anticoagulation should continue with LMWH or whether the patient should be placed on warfarin. Among patients with idiopathic, unprovoked VTE, the recurrence rate is high after cessation of anticoagulation. VTE that occurs during long-haul air travel is considered unprovoked. It appears that unprovoked VTE is often a chronic illness, with latent periods between flares of recurrent episodes. American College of Chest Physicians (ACCP) guidelines recommend considering anticoagulation for an indefinite duration with a target INR between 2 and 3 for patients with idiopathic VTE. An alternative approach after the first 6 months of anticoagulation is to reduce the intensity of anticoagulation and to lower the target INR range to between 1.5 and 2. Counterintuitively, the presence of genetic mutations such as heterozygous factor V Leiden and prothrombin gene mutation do not appear to increase the risk of recurrent VTE. 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 and 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-size 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 after placement. 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 who have a prior history of perioperative PE. The filters can be retrieved up to several months after 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, one should administer 500 mL of normal saline. Additional fluid should be infused with extreme caution because 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 for initiating these pressors. Often, a “trial-and-error” approach works best; one should consider norepinephrine, vasopressin, or phenylephrine. Fibrinolysis Successful fibrinolytic therapy rapidly reverses right heart failure and may result in a lower rate of death and recurrent PE by (1) dissolving much of the anatomically obstructing pulmonary arterial thrombus, (2) preventing the continued release of serotonin and other neurohumoral factors that exacerbate pulmonary hypertension, and (3) lysing 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 hours. Patients appear to respond to fibrinolysis for up to 14 days after the PE has occurred. Contraindications to fibrinolysis include intracranial disease, recent surgery, and 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 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 with moderate or severe RV dysfunction, ACCP guidelines for fibrinolysis recommend individual patient risk assessment of the thrombotic burden versus the bleeding risk. Pulmonary Embolectomy The risk of intracranial hemorrhage with fibrinolysis has prompted a renaissance of surgical embolectomy. More prompt referral before the onset of irreversible cardiogenic shock and multisystem organ failure and improved surgical technique have resulted in a high survival rate. A possible alternative to open surgical embolectomy is catheter embolectomy. New-generation catheters are under development. Pulmonary Thromboendarterectomy Chronic thromboembolic pulmonary hypertension occurs in 2–4% of acute PE patients. Therefore, PE patients who have initial pulmonary hypertension (usually diagnosed with Doppler echocardiography) should be followed up at about 6 weeks with a repeat echocardiogram to determine whether pulmonary arterial pressure has normalized. Patients impaired by 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 . The operation requires median sternotomy, cardiopulmonary bypass, deep hypothermia, and periods of hypothermic circulatory arrest. The mortality rate at experienced centers is approximately 5%. Emotional Support Patients with VTE may feel overwhelmed when they learn that they are susceptible to recurrent PE or DVT. They worry about the health of their families and the genetic implications of their illness. Those who are advised to discontinue warfarin after 3–6 months of therapy may feel especially vulnerable. At Brigham and Woman’s Hospital a physican-nurse–facilitated PE support group has been maintained for patients and has met monthly for more than 15 years. Prevention of Postphlebitic Syndrome Daily use of below-knee 30- to 40-mmHg vascular compression stockings will halve the rate of developing postphlebitic syndrome. These stockings should be prescribed as soon as DVT is diagnosed and should be fitted carefully to maximize their benefit. When patients are in bed, the stockings need not be worn. Prevention of VTE Prophylaxis (Table L-5) is of paramount importance because VTE is difficult to detect and poses a profound medical and economic burden. Computerized reminder systems can increase the use of preventive measures and at Brigham and Women’s Hospital have reduced the symptomatic VTE rate by more than 40%. Patients who have undergone total hip or knee replacement or cancer surgery will benefit from extended pharmacologic prophylaxis for a total of 4–5 weeks. Table L-5 Prevention of Venous Thromboembolism Condition Prophylaxis Strategy High-risk general surgery Mini-UFH or LMWH 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); rivaroxaban or dalteparin in countries where it is approved Neurosurgery IPC Neurosurgery for brain tumor Mini-UFH or LMWH, + IPC + predischarge venous ultrasonography Benign gynecologic surgery Mini-UFH Medically ill patients Mini-UFH or LMWH Anticoagulation contraindicated IPC Long-haul air travel Consider LMWH for very high-risk patients Note: Mini-UFH, mini-dose unfractionated heparin, 5000 units subcutaneously twice (less effective) or three times daily (more effective); 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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