Thromboembolic Event

Etiology

The predisposition to thromboembolic disease is multifactorial. Individual patient factors, current disease state, recent or planned surgical procedures, and underlying hematologic disorders all add up to give a patient’s risk of VTE at that particular time. Patient-related factors include age over 40 years, obesity, the presence of varicose veins, and immobility. The use of oral-contraceptive medications and smoking increases the risk of VTE, as well.[2][3] Disease states generally known for increasing risk for VTE are malignancies, spinal cord injuries with paralysis, and nephrotic syndrome.[4][5] However, the presence of congestive heart failure,[6] inflammatory bowel disease,[7], and a recent myocardial infarction also confer a higher risk of VTE.[8] The presence of pelvic, hip, or long-bone fractures, along with orthopedic surgeries involving the hip and knee, all increase the risk of VTE as well. Hematologic disorders that lead to hypercoagulability include activated protein C resistance (factor V Leiden mutation), protein C or protein S deficiency, antithrombin III deficiency, presence of lupus anticoagulant, dysfibrinogenemia, prothrombin mutation, polycythemia vera, and paroxysmal nocturnal hemoglobinuria. The physiologic state of pregnancy also confers a higher risk of VTE. 

Multiple risk assessment models have now been developed to identify those at the highest risk of hospital-acquired VTE and to provide appropriate thromboprophylaxis for these patients. The Caprini model was the first quantitative VTE risk assessment model to be validated and have worldwide use. The Brigham and Women's Hospital Model (Kucher model), the Padua model, Roger’s model, the Intermountain model, the IMPROVE model, and the Premier model have since undergone development and validation.[9]

Epidemiology

Reviewing available literature reveals the global annual burden of venous thromboembolism to be in millions of cases. The morbidity and mortality associated with these cases are significant, as well. In the United States alone, there are approximately 100000 to 300000 VTE-related deaths reported every year.[10] In Europe, this number rises to greater than 500000 deaths annually by most published reports. The most concerning fact about these numbers is that the majority of these cases are hospital-related or acquired. With 60% of VTE cases being hospital-acquired, VTE is the leading preventable cause of death in hospitalized patients.[11]

Pathophysiology

Venous thrombosis refers to the formation of a platelet and fibrin clot within the vascular lumen. Clinically significant thrombi are formed in vessels with large lumens, such as the deep veins of the legs, pelvis, and arms. The clot can then propagate with proximal extension. Clinical symptoms of the thrombus are seen when the clot propagates enough to have obstruction of vascular flow. If the clot dislodges, it can then embolize to a distant site. The most common site of embolization for these clots is in the pulmonary vasculature. Obstruction to pulmonary vascular flow can cause impaired gas-exchange, alveolar edema, or even pulmonary alveolar necrosis. Chronic repetitive pulmonary embolization can lead to increased pulmonary vascular resistance and, eventually, pulmonary hypertension. In the presence of cardiac abnormalities such as a patent foramen ovale or an atrial septal defect, paradoxical embolism of the clot into the systemic arterial vascular can occur.

History and Physical

With DVT, the patient presents with a complaint of unilateral limb pain. This pain may be accompanied by physical signs of swelling, warmth, and tenderness to touch. However, physical exam signs for the diagnosis of DVT are of low yield. 

With pulmonary embolism (PE), the most common presenting complaint is dyspnea that is sudden in onset. Patients may also demonstrate pleuritic chest pain and cough, as well as hemoptysis in some cases. Massive pulmonary embolism presents with syncope and signs of hemodynamic compromise such as hypotension and shock. Physical examination of patients with PE may reveal hypoxia, tachycardia, and fever. Tachypnea, with a respiratory rate over 18/min, is the most common sign of PE. However, in general, physical exam findings for PE are variable and nondiagnostic. The presence of confounding factors such as sickle cell disease may complicate presentation even further. In these patients, PE usually presents with a chest infection. In older patients, new-onset atrial fibrillation may be the presenting symptom of a PE and requires exclusion in such cases. 

In patients with established PE, tachypnea (respiratory rate over 18/min) is the most common physical findings. The pulmonary exam may reveal rales in up to 50% of the cases with an accentuated second heart sound. Tachycardia (heart rate over 100/min) and fever are present in about 45% of the patients. Diaphoresis and an S3 or S4 gallop may be audible in about 30% of the patients. A pleural friction rub may be present in cases with pleuritic chest pain, which suggests a peripheral PE and is often associated with pulmonary necrosis.

Patients with chronic recurrent venous thromboembolism syndromes may present with signs of pulmonary hypertension and cor pulmonale. Dyspnea will be the most common presenting complaint in these patients. The physical exam may reveal a palpable impulse over the second left intercostal space, a loud P2, a right ventricular S3 gallop, and a systolic murmur on inspiration at the left sternal border from tricuspid regurgitation. Hepatomegaly and dependent pitting edema may also occur. 

However, due to the poor sensitivity and specificity of clinical signs and symptoms for DVT and PE, clinical decision-making tools have been developed to identify those with a high pretest probability of VTE; this is possible using the Modified Well’s criteria. The patient suspected of having venous thromboembolism is given points for the presence of predisposing criteria. This includes 3 points for clinical signs or symptoms of DVT, 3 points if an alternative diagnosis is less likely than PE, 1.5 points for heart rate 100 beats per minute or more, 1.5 points for immobilization (over 3 days) or surgery in the preceding 4 weeks, 1.5 points for a previous history of DVT or PE, and 1 point each for hemoptysis and active cancer in the last 6 months. Patients who score less than 2 points have low risk, a score of 2 to 6 points qualifies as moderate risk, and a score greater than 6 equates to high risk according to the original Well's criteria. The Modified Well's criteria simplified the probability using 4 points as the cut-off. Patients with greater than or equal to 4 points are considered to have PE as the probable cause of the presentation.[12] 

Patients suspected of having VTE but score low on the pretest probability scoring can undergo assessment via the highly sensitive D-dimer assay due to its high negative predictive value. Those suspected of having VTE and have a high pretest probability of the disease should be evaluated using definitive testing.[13]

Evaluation

Definitive Testing for VTE

Individuals that have a low pretest probability for VTE may be ruled out using a high sensitivity D-dimer assay.[13] The D-dimer assay has a high negative predictive value but low sensitivity and should thus rule out the disease. However, D-dimer assay cannot be used to diagnose VTE.

Pulmonary angiography has traditionally been the gold standard for the diagnosis of PE; however, due to its invasive nature, it is no longer used on a routine basis. An elevated D-dimer, in suspected cases of PE, needs to be followed by a ventilation-perfusion (VQ) scan or a computed tomography pulmonary angiography (CTPA) to confirm the diagnosis of PE. Individuals with a moderate or high Modified Well’s score should be evaluated directly using CTPA or a VQ scan if a CTPA is contraindicated.

In high pretest probability for DVT or an elevated D-dimer in cases suspected of having DVT, proximal or whole-leg ultrasonography should be used to confirm the diagnosis. Serial ultrasonography is an option if the initial ultrasonogram is negative and suspicion for DVT remains high.[13] 

It is important to note that high sensitivity D-dimer assay is a marker of fibrinolysis and can appear elevated in pneumonia, cancer, sepsis, and recent surgery. It can also be elevated in patients with poor renal function and varies considerably with advanced age as well. An age-adjusted D-dimer cutoff value can be useful in patients with advanced age.[14] Patients suspected of having a PE but who are low risk may have the PERC rule applied to rule out PE. If they meet all criteria, a d-dimer is avoidable, and PE is ruled out on a clinical basis.

The American College of Radiology considers CTPA as the standard of care for the detection of PE. The advantage of this imaging modality, in addition to the diagnosis of the disease, is that it provides important additional information. The spiral (helical) CT scan may suggest an alternative diagnosis if present; this is an advantage when compared to pulmonary angiography or scintigraphy.[15]

The PERC Rule

This rule was established to avoid excessive testing and to avoid the high frequency of false-positive readings in low-risk patients. Kline et al. developed this clinical tool in 2004 which identified the presence of age below 50 years, pulse less than 100 beats per minute, arterial oxygen saturation (SpO2) greater than 94 %, no unilateral leg swelling, no hemoptysis, no recent trauma or surgery, no prior PE or deep venous thrombosis (DVT) and no exogenous estrogen use as low-risk factors for VTE, specifically PE. If a patient fulfills all these criteria, he is considered PERC-negative and is at low risk for PE. In this individual positive D-Dimer is likely to be a false-positive and should be avoided. Kline et al. reported that the prevalence of PE in these cases was 1.4%. Two meta-analyses confirmed the benefits and safety of the PERC rule, with less than 1 % PE in PERC-negative patients after one year of follow up.[16]

Additional Studies

The use of other laboratory tests (such as arterial blood gas, troponin level, and serum brain-natriuretic peptide) or diagnostic studies (such as chest X-ray or electrocardiogram) is of low yield for the general population.

Arterial blood gas (ABG) may reveal hypoxemia, hypocapnia, and respiratory alkalosis, which has poor positive predictive value for the diagnosis of PE. In high-risk settings, however, such as a patient with post-operative respiratory distress, in whom other causes of dyspnea have been ruled out (such as infection and pulmonary edema), the low partial pressure of oxygen (PaO2) may have significant predictive value for PE. In the general population, the ABG derived hypoxemia has little predictive value for PE because other conditions are more likely to lower PaO2 in these cases than PE. 

Serum troponin levels may be elevated in patients with a moderate to large PE due to acute right ventricular myocardial stretch. However, troponin levels do not have a role in the diagnosis of PE and are not a recommended part of a routine diagnostic workup. In patients with established PE, however, elevated serum troponin levels may be associated with higher mortality.[17]

Brain natriuretic peptide (BNP) level is neither sensitive nor specific for PE. However, an elevated level of BNP correlates with an increased risk of subsequent complications and increased mortality in patients with acute PE.

There is no specific role for electrocardiogram (ECG) in the evaluation of a patient with VTE/PE. The clinical utility of ECG lies in rule out acute myocardial infarction in a patient who presents with chest pain, dyspnea, and perhaps other signs of PE. The ECG in most PE cases is normal except for the presence of tachycardia and non-specific ST-T wave abnormalities. The classical findings of S1 Q3 T3 have poor specificity for PE. If significant right heart strain is present with acute cor pulmonale, the ECG may reveal tall, peaked P waves in lead II, a rightward axis deviation; right bundle-branch block; and an S1 Q3 T3 pattern; or atrial fibrillation. 

Echocardiography is indicated in cases of massive PE to evaluate for signs of right-heart strain. It allows visualization and dynamic evaluation of the right ventricle and aid in the assessment of pulmonary arterial pressures. Echocardiography in these cases provides a prognostic assessment, as increased mortality is associated with the presence of right ventricular dysfunction on echocardiography in these cases. Findings of right heart strain on echocardiography include right ventricular enlargement, right ventricular hypokinesis, leftward septal shift, and evidence of pulmonary hypertension. If the right ventricular dysfunction appears on echocardiography, the diagnosis of acute submassive or massive pulmonary embolism is confirmed. Although it may also provide useful information in the identification of alternative diagnoses, it is not a recommended part of a routine workup for PE. 

The American College of Radiology recommends chest radiography as a study for ruling out other causes of chest pain in patients with suspected pulmonary embolism. Chest radiographs, although abnormal in most cases, provide little diagnostic information for the disease. The classic findings of a wedge-shaped pulmonary infarct seen as a pleura-based triangular opacity pointing towards the hilus (also known as the Hampton hump) or decreased pulmonary vascularity (also known as the Westermark sign) seldom present.

Treatment / Management

Anticoagulation remains the primary treatment for VTE (DVT and PE). Thrombolytic therapy and intravenous filter placement are options reserved for specialized cases. In general, the use of direct-acting oral anticoagulants, such as apixaban, dabigatran, edoxaban, and rivaroxaban, is preferred over parenteral heparin and vitamin K antagonist therapy. It is imperative to note that traditional vitamin K antagonists are not effective without concomitant parenteral heparin therapy for at least 5 to 7 days. Also, dabigatran and edoxaban have not yet had testing in acute VTE without previous parenteral heparin therapy. Apixaban and rivaroxaban are both United States Food and Drug Association (U.S. FDA) approved for monotherapy for acute VTE, including both acute DVT and acute PE episodes. 

The duration of therapy for the initial episode of VTE (DVT or PE) remains 3 to 6 months, except for patients with isolated distal DVT and a low risk of recurrence.[18] According to recommendations by the European Society of Cardiology, these patients can safely receive therapy with a short 4 to 6-week course of anticoagulation.[19] Alternative treatment for this group includes no anticoagulation and surveillance compression ultrasound. (B3)

Patients without cancer should receive therapy with direct oral anticoagulants or warfarin. In obese patients who have treatment with low-molecular-weight heparin for the treatment of acute VTE, the American Society of Hematology recommends using their actual weight rather than a “capped” dose.[18] In cancer patients, low-molecular-weight heparin is the drug of choice for the treatment of acute VTE.[20](A1)

In pregnant patients, low molecular-weight heparin is the drug of choice for initial and long-term treatment as well. The duration of treatment in the pregnant patient is at least 6 weeks postpartum with a minimum of 3 months of the total duration of treatment.[21] (B3)

Vena cava filters should only be a consideration if there is a contraindication to anticoagulation. Due to the inferior efficacy of these filters in preventing thromboembolic events, experts recommend a periodic reassessment of these contraindications to anticoagulation.

Thrombolytic therapy is indicated for patients with massive PE causing hemodynamic instability. However, it is essential to note the absolute and relative contraindications for the use of thrombolytic treatment before its application. DVT cases with complete obstruction of blood flow with impending compartment syndrome should also merit consideration for thrombolytic therapy. 

Therapy for recurrent VTE is lifelong anticoagulation. 

Inpatient vs. Outpatient Treatment

Given the inherent risk of hospitalizations, current guidelines increasingly recommend outpatient therapy when possible. Almost all patients with DVTs can have diagnosis and treatment without hospitalization. For PE, clinical tools have been developed to identify those patients that are safely treatable as an outpatient. The Pulmonary Embolism Severity Index (PESI) predicts clinical severity for patients with PE using a patient's age, gender, history of malignancy, history of congestive heart failure or chronic lung disease, and patient's vital signs on presentation. Patients with a low PESI score can safely receive treatment for PE as an outpatient. A simplified version of the PESI score defines low-risk patients as those who are younger than 80 years and have no significant comorbidity with a pulse rate of less than 110/min, systolic blood pressure greater than 100 mm Hg, and oxygen saturation greater than 90% on room air on presentation. 

Differential Diagnosis

Localized symptoms of DVT can be similar to cellulitis, arterial insufficiency, lymphedema, and hematoma.

Patients with PE can have a varied presentation and a broad differential. Congestive heart failure, acute respiratory distress syndrome, pneumonia, and myocardial infarction are always on the differential for patients with PE. Therefore, the evaluation of PE must also include an assessment to rule out these conditions as well.

Prognosis

According to the literature, thromboembolic events represent the number one cause of hospital-acquired morbidity and mortality worldwide. The mortality rate is also dependent on underlying comorbidities. Patients admitted to the hospital for acute VTE, especially PE, with multiple comorbidities including heart failure and atrial fibrillation, can have an in-hospital mortality rate as high as 4.5% in the first 30 days.[22] In patients with active malignancy, this number has been reported to be as high as 10%.[23] A significant number of these patients present with clinically significant and hemodynamically unstable VTE. All-cause 30-day mortality in patients who present with unstable PE is reported as high as 14%.[24] The rate of recurrence also depends on the underlying patient characteristics and predisposing factors to VTE. According to a recent study, the 5-year incidence of recurrent VTE was 17.7% in patients with active cancer and 8.6% in those without cancer.[25] Due to the sheer number of VTE events worldwide on an annual basis and the statistics mentioned above in regards to its mortality and recurrence, an overhaul of thromboprophylaxis policies is necessary to consistently and accurately treat those at the highest risk of the disease. A subset of the population diagnosed with VTE remains at risk for recurrent VTE. Risk factors for VTE recurrence are similar to those required for the initial event and are not necessarily limited to disorders of anticoagulation. Validated and recommended risk prediction models to determine the risk of VTE recurrence include the Vienna model, the DASH score, and the HERDOO-2 model.

Complications

Long term complications of adequately treated VTE are few. The most commonly reported long-term complication is post-thrombotic syndrome in patients diagnosed with DVT, which characteristically presents as pain and swelling of the limb with chronic venous insufficiency.

Longterm sequelae of recurrent PE include pulmonary hypertension and cor pulmonale, as described above.

Bleeding

Bleeding remains the most pertinent and feared complication of the treatment of VTE. Patients with advanced age and underlying hepatic or renal dysfunction are at a higher risk of bleeding. Despite this risk, most guidelines recommend against routine use of laboratory monitoring in patients receiving the newer anticoagulants. For patients receiving vitamin K antagonist therapy and having INR levels monitored, who have a level above 4.5 but under 10 without clinically relevant bleeding, the recommendation is to hold the drug temporarily. Reversal therapy is not a recommendation in this scenario.

If, however, a patient develops life-threatening bleeding with vitamin K antagonist therapy, treatment with intravenous vitamin K along with four-factor prothrombin complex concentrates (PCC) transfusion is the recommended appraoch. For patients receiving newer oral anticoagulant therapy and a life-threatening bleed, transfusion of four-factor PCC transfusion, the clinician can trial recombinant factor Xa infusion or inactivated-zhzo infusion. In some cases where the risk of life-threatening bleeding is high, clinicians may prefer dabigatran of the newer oral anticoagulation agents as idarucizumab is now available for the reversal of this agent. It is important to note that the reocmmendation is for resumption of anticoagulation after a major bleeding episode within 90 days.

Heparin-Induced Thrombocytopenia

Immune-mediated heparin-induced thrombocytopenia (HIT) typically occurs 5 to 10 days after exposure to heparin; this clinically manifests as thrombosis with thrombocytopenia and can be life-threatening. If a patient on heparin therapy has a decline of 50% of more after exposure to heparin, then HIT merits consideration, and antibodies to platelet factor 4 should be checked to make the diagnosis. All heparin containing products should be stopped immediately and should not be given to the patient again. It is important to note that anti-platelet factor 4 is a highly sensitive assay and is used to rule out the disease. If this test is positive, the diagnosis of HIT should be confirmed using the serotonin release assay or the heparin-induced platelet aggregation assay. Treatment for HIT associated thrombosis includes argatroban, bivalirudin, danaparoid, fondaparinux, or a non–vitamin K antagonist oral anticoagulant (such as rivaroxaban). 

Warfarin-Induced Skin Necrosis

Warfarin induced skin necrosis is a rare complication of warfarin therapy and occurs in less than 0.1% of the population. Protein C deficiency is a risk factor for the development of this disorder. In patients with hereditary protein C deficiency, there is a rapid decrease in the concentration of protein C as compared to the other vitamin K-dependent procoagulant factors; this results in a temporary hypercoagulable state which can lead to thrombotic occlusions particularly of the microvasculature. These will clinically manifest as skin necrosis after initiation of warfarin therapy.