# 53 - 290 Deep-Venous Thrombosis and Pulmonary Thromboembolism ### 290 Deep-Venous Thrombosis and Pulmonary Thromboembolism Antihypertensive therapy is the mainstay of therapy for malignant hypertension. With effective BP reduction, manifestations of vascular injury, including microangiopathic hemolysis and renal dysfunction, can improve over time. Whereas prior reports before the era of drug therapy suggested that 1-year mortality rates exceeded 90%, current survival over 5 years exceeds 50%. PART 6 Disorders of the Cardiovascular System Malignant hypertension is less common in Western countries, although it persists in parts of the world where medical care and antihy­ pertensive drug therapy are less available. It most commonly develops in patients with treated hypertension who neglect to take medications or who may use vasospastic drugs, such as cocaine. Renal abnormalities typically include rising serum creatinine and occasionally hematuria and proteinuria. Biochemical findings may include evidence of hemo­ lysis (anemia, schistocytes, and reticulocytosis) and changes associated with kidney failure. African-American males are more likely to develop rapidly progressive hypertension and kidney failure than are whites in the United States. Genetic polymorphisms for APOL1 that are common in the African-American population predispose to focal sclerosing glo­ merular disease, with severe hypertension developing at younger ages secondary to renal disease in this instance. “Hypertensive Nephrosclerosis”  Based on experience with malignant hypertension and epidemiologic evidence linking BP with long-term risks of kidney failure, it has long been believed that lesser degrees of hypertension induce less severe, but prevalent, changes in kidney vessels and loss of kidney function. As a result, a large portion of patients reaching ESRD without a specific etiologic diagnosis are assigned the designation “hypertensive nephrosclerosis.” Pathologic examination commonly identifies afferent arteriolar thickening with deposition of homogeneous eosinophilic material (hyaline arteriolo­ sclerosis) associated with narrowing of vascular lumina. Clinical mani­ festations include retinal vessel changes associated with hypertension (arteriolar narrowing, arteriovenous crossing changes), left ventricular hypertrophy, and elevated BP. The role of these vascular changes in kidney function is unclear. Multiple studies of nephrectomy and biopsy samples from normotensive kidney donors demonstrate changes of nephrosclerosis associated with aging, dyslipidemia, and glucose intol­ erance, with only modest association with BP. Antihypertensive drug therapy does not alter the course of kidney dysfunction identified spe­ cifically as hypertensive nephrosclerosis, although BP reduction does slow progression of proteinuric kidney diseases and is warranted to reduce the excessive cardiovascular risks associated with CKD. ■ ■FURTHER READING Bhalla V et al: Revascularization for renovascular disease: A scientific statement from the American Heart Association. Hypertension 79:e128, 2022. De Mast Q, Beutler JJ: The prevalence of atherosclerotic renal artery stenosis in risk groups: A systemic literature review. J Hypertens 27:1333, 2009. Freedman BI, Cohen AH: Hypertension-attributed nephropathy: What’s in a name? Nat Rev Nephrol 12:27, 2016. Gornik HL et al: First International Consensus on the diagnosis and management of fibromuscular dysplasia. Vasc Med 24:164. 2019. Herrmann SM et al: Management of atherosclerotic renovascular dis­ ease after Cardiovascular Outcomes in Renal Atherosclerotic Lesions (CORAL). Nephrol Dial Transplant 30:366, 2015. Modi KS, Rao VK: Atheroembolic renal disease. J Am Soc Nephrol 12:1781 2001. Parikh SA et al: SCAI expert consensus statement for renal artery stent­ ing appropriate use. Catheter Cardiovasc Interv 84:1163, 2014. Persu A et al: European consensus on the diagnosis and manage­ ment of fibromuscular dysplasia. J Hypertens 32:1367, 2014. Textor SC, Lerman LO: The role of hypoxia in ischemic chronic kidney disease. Semin Nephrol 39:589, 2019. Samuel Z. Goldhaber Deep-Venous Thrombosis and Pulmonary Thromboembolism ■ ■EPIDEMIOLOGY Venous thromboembolism (VTE) encompasses deep-venous throm­ bosis (DVT) and pulmonary embolism (PE) and causes cardiovascular death, chronic disability, and emotional distress. Hospitalizations in the United States have decreased for acute myocardial infarction (MI), heart failure, and stroke among Medicare beneficiaries, but PE hospi­ talizations increased. Pulmonary Embolism Mortality  PE-related mortality in the United States decreased from 6 per 100,000 in 2000 and plateaued at approximately 4.5 per 100,000 in 2017. In contrast, Europe’s age-standardized annual PE-related mortality rate has continued to decrease linearly since 2000. In the United States, PE-related mortal­ ity is increasing among young and middle-aged adults. Consequently, the median age at death from PE decreased from 73 years in 2000 to 68 years in 2018. During this period, the annual PE mortality was up to 50% higher in African Americans compared with Caucasians. Socioeconomic Status  To evaluate the relationship between socioeconomic status and PE, as well as other cardiovascular diseases, 10,942,483 Medicare beneficiaries were studied to determine whether they were hospitalized for PE, MI, heart failure, or stroke between 2003 and 2019. Hospitalizations for MI, heart failure, and stroke declined in socioeconomically disadvantaged and nondisadvantaged communi­ ties. In contrast, PE hospitalizations increased in both disadvantaged and nondisadvantaged communities. The heat map (Fig. 290-1) shows marked regional differences in the rates of PE hospitalization and degrees of social and community disadvantage throughout the United States. By 2019, 30-day mortality was similar between hospitalized beneficiaries from socioeconomically disadvantaged and nondisadvan­ taged communities for MI, heart failure, and ischemic stroke. In con­ trast, mortality among patients hospitalized with PE was consistently higher in disadvantaged areas (Fig. 290-2). This finding may be due, in part, to poor outpatient follow-up and impeded access to anticoagulant medications. Pulmonary Embolism Readmissions   From 2010 to 2018, 721,710 fee-for-service Medicare beneficiaries were hospitalized with PE. The 30-day all-cause readmission rate was 11%, and the 90-day all-cause readmission rate was 15% (Fig. 290-3). The most common reason for readmission was recurrent PE, accounting for about 11% of readmissions within 30 days. COVID-19  In 2020, COVID-19 erupted and caused a global pan­ demic. The most notable clinical feature was a life-threatening acute respiratory syndrome requiring prolonged mechanical ventilation and resulting in a high case–fatality rate. This viral illness was associated with a high incidence of DVT and PE. At autopsy, about one-fourth of PE patients with COVID had both macrovascular and microvascular PE. Contributing etiologies included excessive inflammation with cytokine storm, platelet activation, endothelial dysfunction, and stasis (Fig. 290-4). Long-Term Sequelae of Pulmonary Embolism  With respect to quality of life, about half of PE patients report persistent dyspnea, fatigue, and reduced exercise capacity, and about one-quarter have per­ sistent right ventricular dysfunction on echocardiogram. This constel­ lation of findings is being recognized more frequently and is called the “post-PE syndrome” (Fig. 290-5). A less frequent complication of PE is the development of chronic thromboembolic pulmonary hypertension (CTEPH), which usually causes breathlessness, especially with exertion. Non-disadvantaged: >227.5 Non-disadvantaged: 119.2–173.1 Non-disadvantaged: 0–119.2 Disadvantaged: 0–119.2 Disadvantaged: 119.2–173.1 Disadvantaged: 173.1–227.5 Disadvantaged: >227.5 FIGURE 290-1  Observed hospitalizations for PE are shown per 100,000 Medicare beneficiaries aged 65 year or older residing in socioeconomically disadvantaged (orange) and nondisadvantaged (blue) counties of the United States in 2019. Lower hospitalization rates are represented with lighter shades of each color, and higher hospitalization rates are represented with darker shades. The range of hospitalizations per 100,000 represented by each shade of orange and each shade of blue are shown in the legend. (Reproduced with permission from RK Wadhera et al: Circ Cardiovasc Qual Outcomes 17:e010090, 2024.) Observed 30-day mortality risk 2004 2005 2006 2007 2008 2009 2010 2011 2012 2013 2014 2015 2016 2017 2018 2019 Non-disadvantaged community Disadvantaged community FIGURE 290-2  Trends in 30-day mortality among Medicare beneficiaries hospitalized with pulmonary embolism by community socioeconomic disadvantage from 2003 to 2019. The red lines represent beneficiaries from disadvantaged communities, and the blue line, beneficiaries from nondisadvantaged communities. The bands represent 95% confidence intervals for estimates. Trends in observed 30-day mortality among Medicare beneficiaries hospitalized with cardiovascular conditions by community socioeconomic disadvantage from 2003 to 2019. (Reproduced with permission from RK Wadhera et al: Circ Cardiovasc Qual Outcomes 17:e010090, 2024.) Non-disadvantaged: 173.1–227.5 CHAPTER 290 Deep-Venous Thrombosis and Pulmonary Thromboembolism With 95% Confidence limits Year All cause readmission trends 18.8 20.2 17.7 16.2 (%) PART 6 Disorders of the Cardiovascular System 9.7 11.2 10.2 30-day readmissions 90-day readmissions FIGURE 290-3  Graph showing all-cause readmission rates for pulmonary embolism (PE) patients within 30 days and within 90 days from 2010 to 2018. (Reproduced from M Murthi: Am J Cardiol 184:133, 2022.) Postthrombotic Syndrome  Postthrombotic syndrome (also known as chronic venous insufficiency) damages the venous valves of the leg and worsens quality of life by causing ankle or calf swelling and leg aching, especially after prolonged standing. In its most severe form, postthrombotic syndrome causes deep skin ulceration (Fig. 290-6). ■ ■PATHOPHYSIOLOGY Inflammation  Inflammation takes center stage as a trigger of acute PE and DVT. Inflammation-related risk factors and medical illnesses are now linked as precipitants of VTE (Table 290-1). Prothrombotic States  The two most common autosomal domi­ nant genetic mutations are (1) factor V Leiden, which causes resistance to the endogenous anticoagulant, protein C, and (2) the prothrombin gene mutation, which increases the plasma prothrombin concentration (Chaps. 69 and 122). Antithrombin, protein C, and protein S are natu­ rally occurring coagulation inhibitors. Deficiencies of these inhibitors A B C Risk factors Acute illness Bed-ridden, stasis Genetics Fever Diarrhea Sepsis Liver injury CKD COPD HF Malignancy Sars-COV-2 Inflammatory response Endothelial dysfunction Superinfected Tissue factor TFPI Lymphopenia Inflammatory cytokines IL-6, CRP FIGURE 290-4  Postulated mechanisms of coagulopathy and pathogenesis of thrombosis in COVID-19. A. Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection activates an inflammatory response, leading to release of inflammatory mediators. Endothelial and hemostatic activation ensues, with decreased levels of TFPI and increased tissue factor. The inflammatory response to severe infection is marked by lymphopenia and thrombocytopenia. Liver injury may lead to decreased coagulation and antithrombin formation. B. COVID-19 may be associated with hemostatic derangement and elevated troponin. C. Increased thromboembolic state results in venous thromboembolism, myocardial infarction, or, in case of further hemostatic derangement, disseminated intravascular coagulation. CKD, chronic kidney disease; COPD, chronic obstructive pulmonary disease; CRP, C-reactive protein; FDP, fibrin degradation product; HF, heart failure; IL, interleukin; LDH, lactate dehydrogenase; PT, prothrombin time; TFPI, tissue factor pathway inhibitor. (Reproduced with permission from B Bikdeli et al: COVID-19 and thrombotic or thromboembolic disease: Implications for prevention, antithrombotic therapy, and follow-up. J Am Coll Cardiol 75:2950, 2020.) are associated with VTE but are rare. Antiphospholipid syndrome (APS) is an acquired (not genetic) thrombophilic disorder that predis­ poses to both venous and arterial thrombosis. Patients with APS often warrant lifetime anticoagulation, even if the initial VTE was provoked by trauma or surgery. 19.4 Clinical Risk Factors  Common comorbid VTE risk factors include cancer, obesity, cigarette smoking, systemic arterial hyperten­ sion, chronic obstructive pulmonary disease, chronic kidney disease, long-haul air travel, air pollution, estrogen-containing contraceptives, pregnancy, the first 6–12 weeks postpartum, postmenopausal hormone replacement, surgery, and trauma. A sedentary lifestyle is an increas­ ingly prevalent risk factor. A Japanese study found that each 2 hours per day increment of television watching is associated with a 40% increased likelihood of fatal PE. 11.8 Polygenic Risk Scores  Ghouse and colleagues reported a genomewide association study of VTE that incorporated 81,190 cases and 1,419,671 controls from six cohorts. They identified 93 risk loci, 62 of which were previously unreported. Many risk loci affected the coagu­ lation cascade or platelet function. A VTE polygenic risk score (PRS) enabled identification of both high- and low-risk individuals. Individu­ als within the top 0.1% of PRS distribution had a VTE risk similar to homozygous or compound heterozygous carriers of factor V Leiden or the prothrombin gene mutation. In contrast, in the bottom 10% of the PRS distribution, factor V Leiden and prothrombin gene mutation carriers had a VTE risk similar to that of the general population. PRS improved individual risk prediction beyond that of genetic and clini­ cal risk factors. Some risk factors for arterial thrombosis, such as body mass index and smoking, were concordant with VTE risk, whereas others, such as blood pressure and triglyceride levels, were discordant. Activated Platelets  Virchow’s triad of venous stasis, hypercoagu­ lability, and endothelial injury, usually coupled with an inflammatory trigger, leads to recruitment of activated platelets, which release mic­ roparticles. These microparticles contain proinflammatory mediators Hemostatic abnormalities Clinical outomes Pulmonary microthrombi Intravascular coagulopathy Myocardial injury Cardiac biomarkers Venous thromboembolism D-dimer, FDPs, PT Platelets Myocardial infarction Disseminated intravascular coagulation Description Flowchart for patient self-report of the Post-VTE Functional Status scale PVFS scale grade All usual duties/activities at home or at work can be carried out at the same level of intensity. Symptoms, pain and anxiety are absent. No functional limitations Can you live alone without any assistance from another person? (e.g., independently being able to eat, walk, use the toilet and manage routine daily hygiene) All usual duties/activities at home or at work can be carried out at the same level of intensity, despite some symptoms, pain, or anxiety. Negligible functional limitations Some usual duties/activities at home or at work are carried out at a lower level of intensity or are occasionally avoided due to symptoms, pain, or anxiety. Slight functional limitations Usual duties/activities at home or at work have been structurally modified (reduced) due to symptoms, pain, or anxiety. Moderate functional limitations Assistance needed in activities of daily living due to symptoms, pain, or anxiety: nursing care and attention are required. Severe functional limitations Grade 0 Death Death occurred before the scheduled assessment. D FIGURE 290-5  Flow chart for patient self-report of the Post-Venous Thromboembolism (VTE) Functional Status scale. (Reproduced with permission from GJAM Boon et al: Thromb Res 190:45, 2020, Figure 2.) that bind neutrophils, stimulating them to release their nuclear material and form web-like extracellular networks called neutrophil extracellular traps. These prothrombotic networks contain histones that stimu­ late platelet aggregation and promote platelet-dependent thrombin FIGURE 290-6  Skin ulceration in the medial malleolus from postthrombotic syndrome of the leg. CHAPTER 290 Yes No Are there duties/activities at home or at work which you are no longer able to perform yourself? Deep-Venous Thrombosis and Pulmonary Thromboembolism No Yes Do you suffer from symptoms, pain, or anxiety? Yes No Do you need to avoid or reduce duties/ activities or spread these over time? No Yes Grade 1 Grade 2 Grade 3 Grade 4 generation. Venous thrombi form and flourish in this environment of stasis, low oxygen tension, and upregulation of proinflammatory genes. Interaction Between Venous Thromboembolism and Atherothrombosis  VTE (red clot) and arterial thrombotic (white clot) events were previously considered separate entities. However, the presence of carotid artery plaque is associated with double the risk of incident VTE. This observation led to the discovery of a broad interac­ tion of VTE with acute coronary syndrome and with acute ischemic stroke (Fig. 290-7). These three vascular conditions share similar risk factors and similar pathophysiology: inflammation, hypercoagulability, and endothelial injury. Patients who suffer VTE are more than twice TABLE 290-1  Inflammation-Linked Conditions That Can Trigger PE or DVT Ulcerative colitis Crohn’s disease Rheumatoid arthritis Psoriasis Diabetes mellitus, type 2 Obesity/metabolic syndrome Hypercholesterolemia, especially elevated LDL cholesterol Lipoprotein(a) Pneumonia Acute coronary syndrome Acute stroke Cigarette smoking Sepsis/septic shock Erythropoiesis-stimulating agents Blood transfusion Cancer Abbreviations: DVT, deep-venous thrombosis; LDL, low-density lipoprotein; PE, pulmonary embolism. PE PE PART 6 Disorders of the Cardiovascular System MI MI Stroke Stroke Inflammation: A common underlying process FIGURE 290-7  Broad interaction between venous thromboembolism and atherothrombosis. MI, myocardial infarction; PE, pulmonary embolism. as likely to have a future MI or stroke. Conversely, patients with MI or stroke are more than twice as likely to suffer a future VTE. Embolization  When DVTs (Fig. 290-8) detach from their site of formation, they embolize to the vena cava, right atrium, and right ven­ tricle and lodge in the pulmonary arterial circulation, thereby causing acute PE. Many patients with PE have no evidence of DVT because the leg thrombus has already embolized to the lungs. Paradoxically, these thrombi occasionally embolize to the arterial circulation through a pat­ ent foramen ovale or atrial septal defect. Physiology  The most common gas exchange abnormalities are arterial hypoxemia and an increased alveolar-arterial O2 tension gra­ dient, which represent the inefficiency of oxygen 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 (Fig. 290-9). Other pathophysiologic abnormalities include: 1. Increased pulmonary vascular resistance due to vascular obstruction or platelet secretion of vasoconstricting neurohumoral agents such as serotonin. Release of vasoactive mediators can produce venti­ lation-perfusion mismatching at sites remote from the embolus, thereby accounting for discordance between a small PE and a large alveolar-arterial O2 gradient. 2. Impaired gas exchange due to increased alveolar dead space from vascular obstruction, hypoxemia from alveolar hypoventilation rela­ tive to perfusion in the nonobstructed lung, right-to-left shunting, or impaired carbon monoxide transfer due to loss of gas exchange surface. 3. Alveolar hyperventilation due to reflex stimulation of irritant receptors. FIGURE 290-8  Deep-venous thrombosis at autopsy. RV pressure overload RV wall tension RV dysfunction RV ischemia or infarction LV preload Coronary perfusion LV Cardiac output Systemic pressure FIGURE 290-9  Pathophysiology of pulmonary embolism (PE). LV, left ventricular; RV, right ventricular. 4. Increased airway resistance due to constriction of airways distal to the bronchi. 5. Decreased pulmonary compliance due to lung edema, lung hemor­ rhage, or loss of surfactant. Pulmonary Hypertension, Right Ventricular (RV) Dysfunction, and RV Microinfarction  Pulmonary artery obstruction and neu­ rohumoral mediators cause a rise in both pulmonary artery pressure and pulmonary vascular resistance. When RV wall tension rises, RV dilation, stretch, and dysfunction ensue, with release of the cardiac biomarker brain natriuretic peptide. The interventricular septum bulges into and compresses an intrinsically normal left ventricle (LV). Dia­ stolic LV dysfunction reduces LV distensibility and impairs LV filling. Increased RV wall tension also compresses the right coronary artery, limits myocardial oxygen supply, and precipitates right coronary artery ischemia and RV microinfarction, with release of cardiac biomarkers such as troponin. Underfilling of the LV may lead to a fall in LV cardiac output and systemic arterial pressure, with consequent circulatory col­ lapse and death (Fig. 290-9). ■ ■CLASSIFICATION OF PULMONARY EMBOLISM AND DEEP-VENOUS THROMBOSIS Pulmonary Embolism  Massive (high-risk) PE accounts for 5–10% of cases and is usually characterized by systemic arterial hypotension and extensive thrombosis affecting at least half of the pulmonary vas­ culature. Dyspnea, syncope, hypotension, and cyanosis are hallmarks of massive PE. Patients with massive PE may present in cardiogenic shock and can die from multisystem organ failure. Submassive (intermediaterisk) PE accounts for 20–25% of patients and is characterized by RV dysfunction despite normal systemic arterial pressure. The combina­ tion of right heart failure and release of cardiac biomarkers such as troponin indicates a high risk of clinical deterioration. Low-risk PE constitutes about 65–75% of cases. These patients have an excellent prognosis. Deep-Venous Thrombosis  Lower extremity DVT usually begins in the calf and can propagate proximally to the popliteal, femoral, and iliac veins. Leg DVT is ~10 times more common than upper extremity DVT, which is often precipitated by placement of pacemakers, internal cardiac defibrillators, or indwelling central venous catheters. The likeli­ hood of upper extremity DVT increases as the catheter diameter and number of lumens increase. Superficial venous thrombosis usually presents with erythema, ten­ derness, and a “palpable cord”; it is most common in the lower extremi­ ties because of varicose veins and in the upper extremities because of indwelling intravenous catheters. Superficial veins may be visible in the chest wall (Urschel’s sign). Patients are at risk for extension of the superficial vein thrombosis to the deep-venous system. ■ ■DIAGNOSIS Clinical Evaluation  PE is known as “the great masquerader.” Diagnosis is difficult because symptoms and signs are nonspecific. The most common symptom of PE is unexplained breathlessness. When occult PE occurs concomitantly with overt congestive heart failure or pneumonia, clinical improvement often fails to ensue despite standard medical treatment of the concomitant illness. This scenario provides a clinical clue to the possible coexistence of PE. With DVT, the most common symptom is a cramp or “charley horse” in the lower calf that persists and intensifies over several days. Wells Point Score criteria, validated in ambulatory patients but not in hospitalized patients, help estimate the clinical likelihood of DVT and PE (Table 290-2). Patients with a low likelihood of DVT or a low-tomoderate likelihood of PE should undergo initial diagnostic evaluation with d-dimer testing alone (see “Blood Tests”), without obligatory imaging tests if the d-dimer test result is normal (Fig. 290-10). How­ ever, patients with a high clinical likelihood of VTE should skip d-dimer testing and undergo imaging as the next step in the diagnostic algorithm. Clinical Pearls  Not all leg pain is due to DVT, and not all dyspnea is due to PE (Table 290-3). Sudden, severe calf discomfort suggests a ruptured Baker’s cyst. Fever and chills often herald cellulitis rather than DVT. Physical findings, if present, may consist only of mild palpation discomfort in the lower calf. However, massive DVT often presents with marked thigh swelling, tenderness, and erythema. If a leg is dif­ fusely edematous, DVT is unlikely, except for the most serious form of DVT, phlegmasia cerulea dolens. Recurrent left thigh edema, especially in young women, raises the possibility of May-Thurner syndrome, with right proximal iliac artery compression of the left proximal iliac vein. This syndrome may be associated with a DVT. Upper extremity venous thrombosis may present with asymmetry in the supraclavicular fossa or in the circumference of the upper arms. Pulmonary infarction usually indicates a small PE. This condition is exquisitely painful because the thrombus lodges peripherally, near the innervation of pleural nerves. Nonthrombotic PE 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 TABLE 290-2  Clinical Decision Rules Low Clinical Likelihood of DVT if Point Score Is Zero or Less; Moderate Likelihood if Score Is 1 to 2; High Likelihood if Score Is 3 or Greater CLINICAL VARIABLE DVT SCORE Active cancer Paralysis, paresis, or recent cast Bedridden for >3 days; major surgery <12 weeks Tenderness along distribution of deep veins Entire leg swelling Unilateral calf swelling >3 cm Pitting edema Collateral superficial nonvaricose veins Alternative diagnosis at least as likely as DVT –2 High Clinical Likelihood of PE if Point Score Exceeds 4 CLINICAL VARIABLE PE 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 Abbreviations: DVT, deep-venous thrombosis; PE, pulmonary embolism. Suspect DVT or PE Assess clinical likelihood CHAPTER 290 DVT PE Deep-Venous Thrombosis and Pulmonary Thromboembolism Not low Not high High Low D-dimer D-dimer Normal High Normal High No DVT Imaging test needed No PE Imaging test needed FIGURE 290-10  How to decide whether diagnostic imaging is needed. For assessment of clinical likelihood, see Table 290-2. DVT, deep-venous thrombosis; PE, pulmonary embolism. can embolize, such as hair, talc, and cotton. Amniotic fluid embolism occurs when fetal membranes leak or tear at the placental margin. Nonimaging Diagnostic Modalities  •  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 an abnormally elevated d-dimer is >95% for PE. A normal d-dimer is a useful “rule out” test for PE in patients with low pretest probability. However, the d-dimer assay is not specific. Levels increase in patients with MI, pneumonia, sepsis, cancer, and the postoperative state, and those in the second or third trimester of pregnancy. Therefore, d-dimer testing rarely has a useful role among hospitalized patients because levels are frequently elevated due to systemic illness. The upper limit of normal for d-dimer was considered to be 500 ng/mL; however, guidelines now recommend use of an ageadjusted d-dimer when ruling out acute PE. The age-adjusted d-dimer applies to patients older than 50 years of age with low or intermedi­ ate clinical probability of PE. To calculate the upper limit of normal d-dimer in these patients, multiply the age by 10. For example, a 70-year-old patient suspected of PE would have 700 ng/mL as the upper limit of normal for d-dimer. Implementing routine use of the TABLE 290-3  Differential Diagnosis of DVT and PE DVT Ruptured Baker’s cyst Muscle strain/injury Cellulitis Acute postthrombotic 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 Vasovagal syncope Abbreviations: DVT, deep-venous thrombosis; PE, pulmonary embolism. I aVR PART 6 Disorders of the Cardiovascular System aVL II aVF III II FIGURE 290-11  Electrocardiogram with both the S1Q3T3 sign and T-wave inversions in leads V1-V4—typical of an anatomically large pulmonary embolism. This patient’s CT pulmonary angiogram is shown as Fig. 290-13A and B. age-adjusted d-dimer reduces the number of computed tomogra­ phy (CT) pulmonary angiograms that are ordered. However, the age-adjusted d-dimer does not apply to patients suspected of acute DVT. ELEVATED CARDIAC BIOMARKERS  Serum troponin increases because of RV microinfarction. Myocardial stretch causes release of brain natri­ uretic peptide or NT-pro-brain natriuretic peptide. ELECTROCARDIOGRAM  The most frequently cited abnormality, in addition to sinus tachycardia, is the S1Q3T3 sign: an S wave in lead I, a Q wave in lead III, and an inverted T wave in lead III (Chap. 247). This finding is relatively specific but insensitive. RV strain and ischemia cause the most common abnormality, T-wave inversion in leads V1 to V4 (Fig. 290-11). Noninvasive Imaging Modalities  •  VENOUS ULTRASONOGRAPHY Ultrasonography of the deep-venous system relies on loss of vein compressibility as the primary diagnostic criterion for DVT. When a normal vein is imaged in cross-section, it readily collapses with gentle manual pressure on the ultrasound transducer. This creates the illusion No Compression CFA CFV FIGURE 290-12  Venous ultrasound, with and without compression of the leg veins. CFA, common femoral artery; CFV, common femoral vein; GSV, great saphenous vein; LT, left. V1 V4 V2 V5 V3 V6 of a “wink.” With acute DVT, the vein loses its compressibility because of passive distention by acute thrombus. The diagnosis of acute DVT is even more secure when thrombus is directly visualized; it appears homogeneous, is located in the center of the vein, and has low echo­ genicity (Fig. 290-12). The vein itself often appears mildly dilated, and collateral channels may be absent. Venous flow dynamics can be examined with Doppler imaging. Normally, manual calf compression causes augmentation of the Dop­ pler flow pattern. Loss of normal respiratory variation is caused by an obstructing DVT or by any obstructive process within the pelvis. For patients with a technically poor or nondiagnostic venous ultrasound, consider alternative imaging modalities such as CT and magnetic resonance imaging. CHEST ROENTGENOGRAPHY  A normal or nearly normal chest x-ray often occurs in PE. Well-established abnormalities include focal olige­ mia (Westermark’s sign), a peripheral triangular-shaped density usually located at the pleural base (Hampton’s hump—which is usually due to pulmonary infarction), and an enlarged right descending pulmonary artery (Palla’s sign). Compression CFA CFV A RV LV B FIGURE 290-13  A. Massive bilateral proximal pulmonary embolism on an axial chest CT image in a 53-year-old man (whose electrocardiogram is shown in Fig. 290-11) with filling defects in the right and left main pulmonary arteries (white arrows). B. Four-chamber view in the same patient showing the right ventricle (RV) larger than the left ventricle (LV). CHEST CT  CT pulmonary angiography with intravenous contrast is the principal imaging test for the diagnosis of PE (Fig. 290-13A). Thin-cut chest CT images can provide exquisite detail, with ≤1 mm of resolution during a short breath hold. Sixth-order branches can be visualized with resolution superior to that of conventional invasive contrast pulmonary angiography. The CT scan also provides an excel­ lent four-chamber view of the heart (Fig. 290-13B). RV enlargement on chest CT indicates an increased likelihood of death within the next 30 days compared with PE patients who have normal RV size (commonly defined as a right to left ventricular diameter ratio >1). In patients without PE, the lung parenchymal images may establish alter­ native diagnoses not apparent on chest x-ray that explain the present­ ing symptoms and signs, such as pneumonia, emphysema, pulmonary fibrosis, pulmonary mass, and aortic pathology. LUNG SCANNING  Ventilation/perfusion lung scanning has become a second-line diagnostic test for PE, used mostly for patients who cannot tolerate intravenous contrast. Small particulate aggregates of albumin labeled with a gamma-emitting radionuclide are injected intravenously and trapped in the pulmonary capillary bed. The perfusion scan defect indicates absent or decreased blood flow, possibly due to PE. Ventila­ tion scans, obtained with a radiolabeled inhaled gas such as xenon or krypton, improve the specificity of the perfusion scan. Abnormal ven­ tilation 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 two or more segmental perfusion defects in the presence of normal ventilation. The diagnosis of PE is very unlikely in patients with normal and nearly normal scans and, in contrast, is ~90% certain in patients with high-probability scans. CHAPTER 290 MAGNETIC RESONANCE (MR) (CONTRAST-ENHANCED) IMAGING  When pelvic or leg ultrasound is equivocal, MR venography with gadolinium contrast is an excellent imaging modality to diagnose DVT. MR pulmo­ nary angiography may detect 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 nor­ mal echocardiograms. However, echocardiography is very useful for detecting conditions that may mimic PE, such as acute MI, pericar­ dial tamponade, and aortic dissection. Transthoracic echocardiogra­ phy rarely images thrombus directly in the main pulmonary artery or the right or left main branches. The best-known indirect sign of PE on transthoracic echocardiography is McConnell’s sign: hypokinesis of the RV free wall with normal or hyperkinetic motion of the RV apex. Deep-Venous Thrombosis and Pulmonary Thromboembolism Invasive Diagnostic Modalities  •  PULMONARY ANGIOGRAPHY  Chest CT pulmonary angiography with contrast (see above) has vir­ tually replaced invasive pulmonary angiography as a diagnostic test. Invasive catheter-based diagnostic testing is reserved for patients with technically unsatisfactory chest CTs and for those in whom an interventional procedure such as catheter-directed thrombolysis or embolectomy is planned. A definitive diagnosis of PE requires visual­ ization of an intraluminal filling defect in more than one projection. Secondary signs of PE include abrupt occlusion (“cut-off”) of vessels, segmental oligemia, avascularity, and a prolonged arterial phase with slow filling and tortuous, tapering peripheral vessels. CONTRAST PHLEBOGRAPHY  Venous ultrasonography has virtually replaced contrast phlebography as the principal diagnostic test for suspected DVT. However, contrast phlebography is used when an interventional procedure is planned. Integrated Diagnostic Approach  An integrated diagnostic approach streamlines the workup of suspected DVT and PE (Fig. 290-14). TREATMENT Deep-Venous Thrombosis UPPER EXTREMITY DVT As peripherally inserted central catheter (PICC) use has increased, so has the rate of upper extremity DVT. This rate can be decreased by more judicious selection of patients who require a PICC, use of single-lumen rather than double- or triple-lumen PICCs, and use of the smallest possible lumen size, ideally 4 French rather than 5 or 6 French. ISOLATED CALF DVT The GARFIELD-VTE Registry recruited 2145 patients with isolated calf DVT and 3846 patients with proximal DVT with or without calf DVT. Isolated calf DVT patients were more likely to have either undergone surgery or have experienced leg trauma, and they were less likely to have active cancer or a prior history of VTE. Almost all isolated calf DVT patients received anticoagulation, and nearly half were anticoagulated for at least 1 year. FIBRINOLYSIS If advanced therapy beyond anticoagulation is warranted, one can utilize clot dissolution or clot extraction therapy with catheterdirected therapy. The open vein hypothesis postulates that patients who receive primary therapy will sustain less long-term damage to venous valves, with consequent lower rates of postthrombotic syndrome. However, the ATTRACT trial randomized 692 patients with femoral or iliofemoral DVT to catheter-directed therapy plus DVT imaging test Venous ultrasound PART 6 Disorders of the Cardiovascular System Diagnostic Nondiagnostic Stop MR CT Phlebography PE imaging test Chest CT Diagnostic Nondiagnostic, unavailable, or unsafe Stop Lung scan Diagnostic Nondiagnostic Stop Venous ultrasound Positive Negative Treat for PE Transesophageal ECHO or MR or invasive pulmonary angiography FIGURE 290-14  Integrated diagnostic approach. CT, computed tomography; DVT, deep-venous thrombosis; ECHO, echocardiography; MR, magnetic resonance; PE, pulmonary embolism. anticoagulation versus usual care with anticoagulation alone. After 2 years of follow-up, there was no overall reduction in postthrom­ botic syndrome in the thrombolysis group. However, there was a trend toward less postthrombotic syndrome among patients with iliofemoral DVT (compared with only femoral DVT) who received catheter-directed thrombolysis compared with anticoagulation alone. COMPRESSION STOCKINGS For patients with swelling of the legs when acute DVT is diag­ nosed, below-knee graduated compression stockings may be pre­ scribed, usually 30–40 mmHg or 20–30 mmHg, to lessen patient discomfort. They should be replaced every 3–6 months because they lose their elasticity. However, prescription of vascular com­ pression stockings in asymptomatic newly diagnosed acute DVT patients does not prevent the development of postthrombotic syndrome. TREATMENT Pulmonary Embolism RISK STRATIFICATION Hemodynamic instability, RV dysfunction on echocardiography, RV enlargement on chest CT, and elevation of the troponin level due to RV microinfarction portend a high risk of adverse clinical outcomes despite anticoagulation. However, in most cases, RV Risk stratify Normotension plus normal RV Normotension plus RV hypokinesis Hypotension Secondary prevention Individualize therapy Primary therapy Anticoagulation plus thrombolysis IVC filter Embolectomy: catheter/surgical Anticoagulation alone FIGURE 290-15  Acute management of pulmonary thromboembolism. IVC, inferior vena cava; PE, pulmonary embolism; RV, right ventricular. function and hemodynamic function remain normal, which por­ tend an excellent prognosis and clinical outcome (Fig. 290-15). ANTICOAGULATION There are three major strategies for anticoagulation: (1) the well-established—but waning—strategy of parenteral anticoagu­ lation with unfractionated heparin (UFH), low-molecular-weight heparin (LMWH), or fondaparinux either as monotherapy or more often “bridged” to warfarin; (2) parenteral anticoagulation, switched after 5 days to dabigatran (a direct thrombin inhibi­ tor) or edoxaban (an anti-Xa agent); or (3) oral anticoagulation monotherapy with rivaroxaban or apixaban (both anti-Xa agents) with a 3-week or 1-week loading dose, respectively. For patients with VTE in the setting of suspected or proven heparin-induced thrombocytopenia, one can choose between two intravenous direct thrombin inhibitors: argatroban (metabolized by the liver) or bivalirudin (metabolized by the kidney), or subcutaneously administered fondaparinux (Table 290-4). Unfractionated Heparin  UFH binds to and accelerates the activity of antithrombin, thus preventing additional thrombus formation. Intravenous UFH is typically dosed to achieve a target activated partial thromboplastin time (aPTT) of 60–80 s, which usually corresponds to a chromogenic anti-Xa level of 0.3–0.7 U/mL. When switching from a direct oral anticoagulant (DOAC) to intravenous UFH, monitor the aPTT, not the chromogenic antiXa assay. However, the anti-Xa assay is more accurate than the aPTT in critically ill patients, APS, pregnancy, and suspected heparin resistance. In patients with normal liver function, use an initial bolus of 80 U/kg as a loading dose of UFH, followed by an initial infusion rate of 18 U/kg per h in patients with normal liver function. The short half-life of UFH is especially useful in patients in whom hourto-hour control of anticoagulation intensity is desired. Heparin also has pleiotropic effects that may decrease systemic and local inflammation. 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 chronic kidney disease. Fondaparinux  Fondaparinux, an anti-Xa pentasaccharide, is essentially an ultra-low-molecular-weight heparin. It is adminis­ tered as a weight-based, once-daily subcutaneous injection in a pre­ filled syringe. No laboratory monitoring is required. Fondaparinux is synthesized in a laboratory and, unlike LMWH or UFH, is not derived from animal products. It does not cause heparininduced thrombocytopenia. For patients with renal dysfunction, the fondaparinux dose must be adjusted downward. TABLE 290-4  Anticoagulation of VTE Non-Warfarin 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 Dalteparin 200 U/kg once daily or 100 U/kg twice daily, with normal renal function, or Tinzaparin 175 U/kg once daily with normal renal function, or Fondaparinux weight-based once daily; adjust for impaired renal function Direct thrombin inhibitors: argatroban or bivalirudin (with suspected or proven heparin-induced thrombocytopenia) Rivaroxaban 15 mg twice daily for 3 weeks, followed by 20 mg once daily with the dinner meal thereafter. For CrCl 15–50 mL/min: 10 mg twice daily. Apixaban 10 mg twice daily for 1 week, followed by 5 mg twice daily thereafter. In patients with at least 2 of the following characteristics: age >80 years, body weight <60 kg, or serum creatinine >1.5 mg/dL, the recommended dose is 2.5 mg orally twice daily. Dabigatran: 5 days of unfractionated heparin, LMWH, or fondaparinux followed by dabigatran 150 mg twice daily with CrCl >30 mL/min. For CrCl 15–30 mL/min: 75 mg twice daily. Edoxaban: 5 days of unfractionated heparin, LMWH, or fondaparinux followed by edoxaban 60 mg once daily with normal renal function, weight >60 kg, in the absence of potent P-glycoprotein inhibitors. For CrCl 15–50 mL/ min: 30 mg once daily. Warfarin Anticoagulation Requires 5–10 days of administration to achieve effectiveness as monotherapy Use full-dose unfractionated heparin, LMWH, or fondaparinux as “bridging agents” when initiating warfarin. Continue parenteral anticoagulation for a minimum of 5 days and until two sequential INR values, at least 1 day apart, achieve the target INR range. Usual start dose is 5 mg Titrate to INR, target 2.0–3.0 Abbreviations: aPTT, activated partial thromboplastin time; CrCl, creatinine clearance; INR, international normalized ratio; LMWH, low-molecular-weight heparin; VTE, venous thromboembolism. Warfarin  This vitamin K antagonist prevents carboxylationdependent activation of coagulation factors II, VII, IX, and X (Chap. 69). The full effect of warfarin is attained after daily therapy for 5–7 days. Overlapping UFH, LMWH, fondaparinux, or parenteral direct thrombin inhibitors during initiation of war­ farin provides therapeutic levels of anticoagulation. Parenteral anticoagulation is discontinued when warfarin has achieved a target international normalized ratio (INR) of 2.5. Warfarin can cause major hemorrhage, including intracranial hemorrhage, even when the INR remains within the desired therapeutic range. Warfarin can also cause “off-target” side effects such as alopecia or arterial vascular calcification. Centralized anticoagulation clinics have improved the efficacy and safety of warfarin dosing. Some patients can self-monitor their INR with a home point-of-care fingerstick machine, and a few can be taught to self-dose their warfarin. Direct Oral Anticoagulants  DOACs are administered in a fixed dose, establish effective anticoagulation within hours of ingestion, do not require laboratory coagulation monitoring or limitation of green leafy vegetables, and have few drug-drug interactions. DOACs should not be prescribed during pregnancy or breastfeed­ ing. Warfarin, not DOACs, is the standard treatment for APS. The efficacy and safety of DOACs remain uncertain in patients with end-stage kidney disease or cirrhosis. Management of Bleeding from Anticoagulants  For life-threatening or intracranial hemorrhage due to heparin or LMWH, administer protamine sulfate. The dabigatran antibody, idarucizumab, is an effective, rapidly acting antidote for dabigatran. Andexanet alfa or protein complex concentrate reverses major bleeding caused by anti-Xa DOACs, but beware of rebound thrombosis. With minor TABLE 290-5  Take-Home Points from the European Society of Cardiology 2019 Pulmonary Embolism Guidelines 1. Terminology such as “provoked” versus “unprovoked” PE/DVT is no longer supported by the guidelines, as it is potentially misleading and not helpful for decision-making regarding the duration of anticoagulation. 2. Extended oral anticoagulation without an end date should be considered for CHAPTER 290 patients with a first episode of PE and: a. No identifiable risk factor b. A persistent risk factor c. A minor transient or reversible risk factor Deep-Venous Thrombosis and Pulmonary Thromboembolism Abbreviations: DVT, deep-venous thrombosis; PE, pulmonary embolism. bleeding, fresh-frozen plasma, vitamin K, or observation without pharmacologic intervention can be considered. Cancer and Venous Thromboembolism  For patients with can­ cer and VTE, prescribe LMWH as monotherapy or a DOAC in the absence of a gastrointestinal cancer, and continue extendedduration anticoagulation until the patient is declared cancer-free. The National Comprehensive Cancer Network guidelines endorse treatment of VTE with apixaban or edoxaban. Duration of Anticoagulation  Data-driven guidelines from the European Society of Cardiology are changing our conceptual approach to determining the optimal duration of anticoagulation (Tables 290-5 and 290-6). We should no longer classify VTE as “provoked” or “unprovoked,” given that many types of provoked VTE have a similar recurrence rate to unprovoked VTE once anti­ coagulation is discontinued. Enduring risk factors such as heart failure, chronic lung disease, and inflammatory bowel diseases can heighten the risk of recurrence. INFERIOR VENA CAVA FILTERS The two principal indications for insertion of an inferior vena cava filter are (1) active bleeding that precludes anticoagulation and (2) recurrent venous thrombosis despite intensive anticoagulation. Prevention of PE in patients who are not candidates for anticoagu­ lation is a much “softer” indication for filter placement. The filter itself may fail by permitting the passage of small- to medium-size clots via collateral veins that develop. Paradoxically, by providing a nidus for clot formation, filters may increase the DVT rate even though they usually prevent PE. In most situations, place a retriev­ able rather than a permanent filter. MANAGEMENT OF MASSIVE PE For patients with massive PE and hypotension, replete volume with 500 mL of normal saline. 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. Norepinephrine and dobutamine are first-line vasopressor and inotropic agents, respectively, for treatment of PErelated shock. Norepinephrine increases systemic arterial pressure. Dobutamine increases RV inotropy and lowers filling pressures. If TABLE 290-6  Risk of Recurrent Venous Thromboembolism After Discontinuing Anticoagulation (European Society of Cardiology 2019 Pulmonary Embolism Guidelines) RISK OF RECURRENCE EXAMPLES Low risk (<3% per year) Major surgery or trauma Intermediate risk (3–8% per year) Minor surgery Hospitalized with acute medical illness Pregnancy/estrogens Long-haul flight Inflammatory bowel disease Autoimmune disease No identifiable risk factor (formerly called “unprovoked”) High risk (>8% per year) Active cancer Antiphospholipid syndrome additional hemodynamic circulatory support is required, available, and within the scope of the patient’s goals of care, consider venoarterial extracorporeal membrane oxygenation (ECMO). FIBRINOLYSIS Successful fibrinolytic therapy rapidly reverses right heart failure and may result in a lower rate of death and recurrent PE by (1) dis­ solving much of the anatomically obstructing pulmonary arterial thrombus, (2) preventing the continued release of serotonin and other neurohumoral factors that exacerbate pulmonary hyperten­ sion, and (3) lysing much of the source of the thrombus in the pelvic or deep leg veins, thereby potentially decreasing the likelihood of recurrent PE. PART 6 Disorders of the Cardiovascular System For massive PE, the U.S. Food and Drug Administration has approved systemically administered 100 mg of recombinant tissue plasminogen activator (tPA) (alteplase) prescribed as a continuous intravenous infusion over 2 h. The sooner thrombolysis is admin­ istered, the more effective it is. However, systemic fibrinolysis can be utilized effectively for at least 14 days after the PE has occurred. A popular but controversial off-label dosing regimen is 50 mg of tPA administered over 2 h. This lower dose appears less effective than full-dose tPA but may be associated with fewer bleeding complications. Contraindications to fibrinolysis include intracranial disease, recent surgery, and trauma. The overall major bleeding rate is ~10%, including a 2–3% risk of intracranial hemorrhage. Careful screening of patients for contraindications to fibrinolytic therapy (Chap. 286) is the best way to minimize bleeding risk. For patients with submassive PE who have preserved systolic blood pressure but moderate or severe RV dysfunction, use of fibrinolysis remains controversial. A 2019 American Heart Associa­ tion Scientific Statement suggests consideration of thrombolysis or embolectomy in patients with a lack of clinical improvement, clini­ cal deterioration, clot in transit, severe or persistent RV strain, or signs of low cardiac output. CATHETER-DIRECTED THERAPY There are three types of catheter-directed therapy to treat VTE: (1) pharmacologic only, (2) mechanical only, or (3) pharmacomechani­ cal. Pharmacologic therapy usually utilizes a low-dose continuous infusion of tPA. Mechanical therapy serves as a percutaneous thrombectomy. The procedure usually employs suction, snaring, and extraction of thrombus without using thrombolytic therapy. One mechanical device is a catheter with expandable nitinol disks that traps the thrombus, which is then removed. Pharmacomechani­ cal therapy is epitomized by low-energy ultrasound-facilitated lowdose thrombolysis. The low-dose thrombolysis strategy most likely explains the lower major bleeding complication rate compared with systemically administered fibrinolysis. SURGICAL PULMONARY EMBOLECTOMY The substantial risk of major hemorrhage with systemically admin­ istered fibrinolysis reawakened interest in alternative treatment with surgical embolectomy, an operation that had almost become extinct. More rapid referral for surgery before the onset of irrevers­ ible multisystem organ failure, improved surgical technique, and utilization of ECMO have increased the survival rate of surgical pulmonary embolectomy and have markedly improved right ven­ tricular function. PULMONARY THROMBOENDARTERECTOMY CTEPH develops in about 2% of acute PE patients. Therefore, PE patients who have initial pulmonary hypertension (often detected initially during echocardiography) should be followed up at about 6 weeks and, if necessary, at 6 months, with repeat echo­ cardiograms to determine whether pulmonary arterial pressure has worsened, plateaued, or abated. Patients impaired by dyspnea due to CTEPH should be considered for pulmonary thromboen­ darterectomy, which can markedly reduce, and sometimes even cure, pulmonary hypertension (Chap. 294). The operation requires TABLE 290-7  Prevention of Venous Thromboembolism Among Hospitalized Patients CONDITION PROPHYLAXIS STRATEGY High-risk nonorthopedic surgery Unfractionated heparin 5000 units SC bid or tid Enoxaparin 40 mg daily Dalteparin 2500 or 5000 units daily Medical oncology (ambulatory) Apixaban or rivaroxaban for up to 6 months in high-risk patients with cancer starting a new chemotherapy regimen Cancer surgery, including gynecologic cancer surgery Enoxaparin 40 mg daily, consider 1 month of prophylaxis Major orthopedic surgery Aspirin 81 mg twice daily Rivaroxaban 10 mg daily, beginning 6–10 h postoperatively Dabigatran 110 mg first day, then 220 mg daily Apixaban 2.5 mg bid, beginning 12–24 h postoperatively Warfarin (target INR 2.0) Enoxaparin 40 mg daily Dalteparin 2500 or 5000 units daily Fondaparinux 2.5 mg daily Medically ill patients, especially if immobilized, with a history of prior VTE, with an indwelling central venous catheter, or with cancer (but without active gastroduodenal ulcer, major bleeding within 3 months, or platelet count <50,000) Unfractionated heparin 5000 units bid or tid Enoxaparin 40 mg daily Dalteparin 2500 or 5000 units daily Fondaparinux 2.5 mg daily Medically ill patients about to be discharged from hospital Rivaroxaban 10 mg daily for about 5 weeks (rarely prescribed for this indication) Anticoagulation contraindicated Intermittent pneumatic compression devices and/ or graduated vascular below-knee compression stockings Abbreviations: INR, international normalized ratio; VTE, venous thromboembolism. median sternotomy, cardiopulmonary bypass, deep hypothermia, and periods of hypothermic circulatory arrest. The mortality rate at experienced centers is 1–5%. Inoperable patients should be man­ aged with pulmonary vasodilator therapy and balloon angioplasty of pulmonary arterial webs. ■ ■PREVENTION OF VTE Prevention of DVT and PE (Table 290-7) is of paramount importance because VTE is difficult to detect and poses a profound medical and economic burden. Low-dose UFH or LMWH is the most common form of in-hospital prophylaxis. Computerized reminder systems in ambulatory and in-hospital practices can increase the use of preventive measures and, at Brigham and Women’s Hospital, have reduced the symptomatic VTE rate. ■ ■EMOTIONAL SUPPORT Patients with VTE may feel overwhelmed when they learn that they are suffering from PE or DVT. Some have never previously encoun­ tered serious cardiovascular illness. They often assume they will have a reduced life expectancy. They worry about the health of their families and the genetic implications of their illness. At Brigham and Women’s Hospital, a physician-nurse–facilitated PE support group was initiated to address these concerns and has met monthly for >30 years. The non­ profit North American Thrombosis Forum (www.thrombosis.org) runs monthly online support groups that garner worldwide participation. ■ ■FURTHER READING Barco S et al: Age-sex specific pulmonary embolism-related mortality in the USA and Canada, 2000–18: An analysis of the WHO Mortality Database and of the CDC Multiple Cause of Death database. Lancet Respir Med 9:33, 2021.