Patients for Thrombolysis

PE confirmed (n = 1880) (%)

PE not confirmed (n = 528) (%)

Symptoms

Dyspnea

Pleuritic chest pain

Substernal chest pain

Syncope

Unilateral leg pain

Signs

Cough

Fever

Hemoptysis

Signs of deep venous thrombosis

Diaphoresis

Respiratory distress

Modified from Pollack et al. J Am Coll Cardiol 2011; 57:700, with permission

Current data coming from EMPEROR registry suggests an “atypical” PE presentation related with emerging risk factors. This was a prospective contemporary registry in Emergency Department patients to identify data specific of race or ethnicity, to compare the availability and contemporaneous use of risk stratification methods, including serum biomarkers and, the frequency of use of empiric anticoagulation, an intervention that may affect outcome [8].

In this study, 1880 acute PE patients were confirmed by computerized tomographic pulmonary angiogram in 88 % of cases. Patients represented both sexes equally, and racial and ethnic composition paralleled the overall US Emergency Department population. An unexpected clinical profile included young male, Caucasian or African American, employed, living independently, with a high incidence of atherosclerosis risk factors, and, with dyspnea on exertion [8]. Additionally, this “atypical” clinical profile had two confounding factors: an increase in the incidence of male gender and dyspnea with exertion. Because effort dyspnea has been related with COPD, heart failure with preserved or not ejection fraction, asthma, ischemic heart disease, and pulmonary arterial hypertension, physicians have to be in warning with this clinical presentation.

Although white-collar employment is usually equivalent with a sedentary lifestyle and long periods of sitting behind a computer (eThrombosis), such a relationship was not explored. Emergency physicians have to be in warning and should not limit their thinking suspicion to the “typical” presentations of PE (chronic or incurable disease, hospitalization, cancer, major surgery, bed-bound, etc.), and avoid misdiagnosis of acute coronary syndromes.

Risk Factors

Current approach to classify risk factors is considering that venous thromboembolism results from both interaction between patient-related risk factor and setting-related risk factors [9–11] (Table 4.2). The first, are considered to be permanent, whereas the second, temporary. Risk factor evidence including age, past history of deep venous thrombosis, major trauma, lower limb fractures, spinal cord injury, left ventricular dysfunction, cancer, chronic obstructive pulmonary disease, and infection can interact predisposing hospitalization and deep venous thrombosis. Interestingly, the predictive weighs for these factors are unequal and venous thromboembolism could occur in patients without any identifiable predisposing factor [10] in up to 30 % of PE patients. In women, oral contraception use, even in reduced dose of estrogen, represent still an increased risk [12]. Pregnancy and postpartum period are related with venous thromboembolism and is an important cause of maternal morbidity and mortality. The risk is highest by the last trimester of pregnancy and 6 weeks after delivery [12–14]. Due to nonspecific presentation, PE could be a challenging ruling-out disorder. However, a prompt stratification and expedite diagnosis are fundamental to offer an early directed treatment. Being aware of patient’s particular profile together with risk factors could help physician choosing a most appropriate stratification and diagnostic approach.

Table 4.2

Risk factors for venous thromboembolism

	Temporary	Permanent
Patient-related risk factors—hereditary
Activated protein C resistance without factor V Leiden		+
Antithrombin deficiency		+
Dysfibrinogenemia		+
Factor V Leiden		+
Protein C deficiency		+
Protein S deficiency		+
Prothrombin gene mutation		+
Plasminogen deficiency		+
Patient-related risk factors—setting
Acute medical illness	+
Advanced age		+
Cancer	+	+
Central venous catheter	+
Chemotherapy	+
Chronic obstructive pulmonary disease		+
Hormonereplacement therapy	+	+
Immobilizer or plaster cast	+
Infection	+
Major surgery	+
Left ventricular dysfunction	+	+
Obesity	+	+
Oral contraceptives	+
Pregnancy and post partum period	+
Prolonged travel (air or ground)	+
Reduced mobility (prolonged)	+	+
Spinal cord injury	+	+
Trauma	+

Current European Cardiology Society guidelines on PE classified the risk factors regarding the odds ratios are as follows: Strong risk factors (odds ratio >10): Fracture of lower limb previous 3 months, hip or knee replacement, major trauma, myocardial infarction (within previous 3 months), previous venous thromboembolism, and spinal cord injury. Moderate risk factors (odds ratio 2–9): arthroscopic knee surgery, auto–immune diseases, blood transfusion, central venous lines, chemotherapy, congestive heart or respiratory failure, erythropoiesis-stimulating agents, hormone replacement therapy (depends on formulation), in vitro fertilization, cancer (highest risk in metastatic disease), oral contraceptive therapy, paralytic stroke, postpartum period, and thrombophilia. Weak risk factors (odds ratio <2): Bed rest >3 days, diabetes mellitus, hypertension, immobility due to sitting (e.g., prolonged car or air travel), increasing age, laparoscopic surgery (e.g., cholecystectomy), obesity, pregnancy, and varicose veins [7]. An interesting observation is that stronger risk factors with odds ratio ranging from <2 to >10 were all involved with inflammation, coagulation cascade, and platelet activation.

From our point of view, risk factors could be classified on molecular bases [15]. A reorganization of the risk factors, taking into account the molecular evidence, is shown in Table 4.3. Inflammation involves several conditions in health and disease related historically with deep venous thrombosis and PE. Secondary thrombophilia includes factors associated with the coagulation cascade and platelet activation to a greater or lesser degree; as well as other mechanisms observed in different clinical situations. Molecular thrombophilia was separated in acquired and hereditary. Finally, independent of the risk factors, stasis or infections are the triggers for acute thromboembolic event.

Table 4.3

Risk factors on molecular bases

Risk factor	Clinical expression
Inflammation	Smoking, obesity, dysglycemia, diabetes mellitus, metabolic syndrome, dyslipidemia, ischemic heart disease, acute coronary syndromes, stroke, peripheral artery disease, hypertension, COPD, acute or chronic heart failure, respiratory failure, atrial fibrillation, connective tissue diseases (systemic lupus erythematosus, rheumatoid arthritis, etc.), renal chronic failure, nephrotic syndrome, Behcet’s disease
Secondary thrombophilia
Coagulation cascade and platelet activation	Fracture, hip or knee replacement, major or minor surgery, major trauma, spinal cord injury, arthroscopic knee surgery, secondary polycythemia, vaginal delivery and cesarean section
Miscellaneous mechanisms	• Physiologic hypercoagulable state: age >40 years, aging, pregnancy, postpartum
	• Procoagulant effects: malignancy
	• Therapeutic action: chemotherapy, hormone replacement and oral contraceptive therapy, pacemaker or implantable cardiac defibrillator leads and indwelling venous catheters, heparin-induced thrombocytopenia
Molecular thrombophilia
Acquired	Lupus anticoagulant, antiphospholipid antibody syndrome, hyperhomocystinemia (less commonly inherited secondary to a mutation in methylenetetrahydrofolate reductase), deficiency of dysfibrinogenemia, myeloproliferative disorders such as polycythemia rubra vera, elevated levels of lipoprotein (a)
Hereditary	Deficiency of antithrombin III, protein C or protein S, factor V Leiden mutation, prothrombin gene mutation, primary thrombocytopenia, hypercoagulability syndromes, deficit or abnormalities of plasminogen, dysplasminogenemia, hyperprothrombinemia, deficiency of factor XII, factor VIII increase, deficiency or abnormalities of plasminogen, increase plasminogen activator inhibitor type-1, paroxysmal nocturnal hemoglobinuria
Triggers	• Stasis: prolonged car or air travel, bed-bound, computer works, or immobilities related to the home: convalescence secondary to chronic heart failure, pulmonary or neurological diseases, cancer, degenerative osteoarthropathy, and obesity
Triggers	• Chronic or acute infections: periodontitis, upper or lower respiratory tract, gastrointestinal, urinary, prostate, etc.

Modified from [15]

Different calculation rules have been validated in predicting probability (low, moderate, or high-clinical probability, PE likely or unlikely) (Table 4.4), and adverse outcome [16, 17] (Table 4.5). These scores account both for the clinical severity of an acute event and the patient’s comorbidity. The Pulmonary Embolism Severity Index (PESI) has been widely validated. One of its major strength is ruling out an adverse outcome as evidenced by the high negative predictive value of the classes II and I. On the other hand, a weak of the original PESI score is the many unequally weighed variables that can become a quite multipart calculate, reducing eventually its workability in an emergency setting. A simplified version (sPESI) assesses only six equally weighed variables and accurately identifies patients with PE who are at low risk of death and other complications [18]. Those patients with moderate or high pretest probability should continue their assessment with an imaging modality.

Table 4.4

Clinical prediction rules for pulmonary embolism

Variable	Clinical decision rule points
Variable	Original version	Simplified version
Wells rule
Previous pulmonary or deep venous thrombosis	1.5	1
Heart rate ≥100 beats per minute	1.5	1
Surgery or immobilization within past 4 weeks	1.5	1
Hemoptysis	1	1
Active cancer	1	1
Clinical signs of deep venous thrombosis	3	1
Clinical probability
Three-level score
Low	0–1	N/A
Intermediate	2–6	N/A
High	≥7	N/A
Two-level score
Pulmonary embolism unlikely	0–4	0–1
Pulmonary embolism likely	≥5	≥2
Revised Geneve score
Previous pulmonary embolism or DVT	3	1
Heart rate
75–94 beat per minute	3	1
≥95	5	2
Surgery or fracture within the past month	2	1
Hemoptysis	2	1
Active cancer	2	1
Unilateral lower limb pain	3	1
Pain on lower limb deep venous and unilateral edema	4	1
Age >65 years	1	1
Clinical probability
Three-level score
Low	0–3	0–1
Intermediate	4–10	2–4
High	≥11	≥5
Two-level score
Pulmonary embolism unlikely	0–5	0–2
Pulmonary embolism likely	≥6	≥3

DVT deep venous thrombosis. Eur Heart J 2014; 35:3033–3080, with permission

Table 4.5

Original, simplified and proposed pulmonary embolism severity index (PESI)

Variable	Original PESI^a Score	Simplified PESI^b Score	Proposed PESI Score
Dyspnea plus near-syncope or syncope			1
Dyspnea plus ischemic-like chest pain			1
Age >80 years	Age in years	1	–
Male sex	+10	–	–
History of cancer	+30	1	–
History of heart failure	+10	1^c	–
History of chronic lung disease	+10	1^c	–
Pulse ≥110 beats per minute	+20	1	1
Systolic blood pressure <100 mmHg	+30	1	1
Respiratory rate ≥30 breaths per minute	+20	–	1
Temperature <36 °C	+20	–	–
Altered mental status^d	+60	–	–
Arterial oxygen saturation <90 %^e	+20	1	1

Modified from Thromb Haemost 2011; 106:423–28

^aA total point score for a given patient is obtained by summing the patient’s age in years and the points for each applicable prognostic variable. The five following risk classes are defined on patient’s total point score: class I (≤65 points), class II (66–85 points), class III (86–105 points), class IV (106–125 points), and class V (>125 points). Patients in risk classes I/II are considered low risk

^bA total point score for a given patient is obtained by summing the patient’s age in years and the points for each applicable prognostic variable. Patients with 0 points are considered low risk

^cThe variables were combined into a single category of chronic cardiopulmonary disease

^dAltered mental status was defined as disorientation, lethargy, stupor, or coma

^eArterial oxygen saturation was defined with and without the administration of supplemental oxygen

Considering that dyspnea plus near-syncope or syncope or dyspnea associated to ischemic-like chest pain in PE patients has been associated with >50 % of pulmonary arterial obstruction in pulmonary angiography and with severe right ventricular dysfunction, respectively, we considered that both conditions could be added to proposed PSI score, maintaining pulse, systolic blood pressure, respiratory rate, and oxygen saturation. This simple tool could be used in emergency department by physicians with or without experience. Our proposal required clinical validation.

Suggestive Electrocardiogram

In the stratification approach, this accessible tool provides important findings to identify severe right ventricular pressure overload and ventricular ischemia. An electrocardiogram never will be normal in submassive or massive PE. The traditional right axis deviation is not always present, specifically during the early state of the acute event. In Fig. 4.1 a normal preoperative ECG, then in-hospital patient had a massive PE complicated with patent foramen ovale and paradoxical embolism to right coronary artery. In Fig. 4.2, there is not a right axis deviation expected in massive PE; however there is almost 60° axis deviation compared with the first electrocardiogram; also other electrocardiogram findings described in massive PE are observed; lead standard DI, aVL, chest leads V2, V3, and V4 ST depression, aVR-ST elevation [19] and chest lead V1 with qR and ST elevation: ST elevation in standard inferior leads are secondary to right coronary paradoxical embolism.

Fig. 4.1

Before surgery normal electrocardiogram

Fig. 4.2

Compared with electrocardiogram in Fig. 4.1, there is right axis deviation and ST depression in DI, aVL, V2 to V3 related with massive pulmonary embolism. Also ST elevation in inferior leads was secondary right coronary artery paroximal embolism. qR in V1 is related with right atrial dilatation. ST elevation in aVR and V1 could be explained for right ventricular ischemia and infarction respectively

In the setting of PE patients, on admission aVR-ST elevation was present in 34.3 % (n = 136). Presence of aVR-ST elevation was associated with more severe clinical presentation (dyspnea at rest 44.9 % vs. 29.2 %; p = 0.002, hypotension 17.0 % vs. 6.5 %; p = 0.001, syncope 16.2 % vs. 6.5 %; p = 0.002), higher median troponin T levels (0.035 [0.01–0.2] vs. 0.01 [0.01–0.02]; p 0.001), more frequent right ventricular dysfunction (74.5 % vs. 46.6 %; p 0.001), and central located thrombi (50.8 vs. 29.2; p 0.001). Thrombolysis was used more frequently (29.1 % vs. 7.5 %; p 0.001) and in-hospital-mortality was increased (10.3 % vs. 5.4 %; p = 0.07) when compared to patients without that sign. Mortality in intermediate-risk PE patients with aVR-ST elevation was 8.9 % compared to 0 % in those without (p = 0.04). In contrast, the presence of other classical electrocardiogram pattern of PE did not further increase mortality in intermediate-risk patients. Finally, ST elevation in lead aVR is associated with a more severe course of PE, especially in patients with intermediate-risk. Therefore, aVR-ST elevation might be useful in risk stratification of PE [20].

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