Venous Thromboembolic Disease August 19, 2009 Henry L. Green, MD, FACC, FACP Venous thrombosis Superficial thrombophlebitis Superficial thrombophlebitis typically presents with a swollen, red superficial vein, often with a palpable cord. About 5% of these patients develop deep thrombophlebitis. When it results from an infusion, the recommended treatment is to apply topical diclofenac gel, or to administer the drug orally. If it develops spontaneously, the guidelines advise intermediate dosages of unfractionated or low molecular weight heparin for four or more weeks. Deep thrombophlebitis Venous thrombosis usually occurs in the lower extremity. Local pain, swelling and tenderness suggest the diagnosis, but often there are no appreciable signs. Thrombophlebitis generally begins in the venous sinuses of the calf muscles. These clots rarely embolize, but 25% of them will propagate to the proximal veins. About 50% of proximal venous thrombi will result in pulmonary emboli. The differential diagnosis of deep vein thrombosis includes the following: Abscess Baker’s cyst Cellulitis Claudication Injury Venous stasis Lymphedema Vasculitis Postphlebitic syndrome Major risk factors: Hypercoagulable states Factor V Leiden mutation Protein C deficiency Protein S deficiency Elevated factor VIII Elevated homocysteine

Antithrombin III deficiency Hyperhomocysteinemia Family history of thromboembolism Prothrombin 20210A mutation Lupus anticoagulant

Other risk factors: Old age Smoking Surgery Trauma Immobilization Long-haul air travel Oral contraceptives Hormone therapy Acute infection Transvenous device Prolonged sitting at computer (“ethrombosis”)

Obesity Pregnancy Malignancy Venous stasis Prior history of thromboembolism

Lower extremity deep venous thrombosis is treated initially with unfractionated or low molecular weight heparin and warfarin. Bed rest is not advised unless there is substantial pain and swelling. Sometimes venous thrombosis develops in the upper extremity as a result of compression, or the presence of an indwelling catheter or a pacemaker wire. Certain athletic endeavors may also induce it. At times, no cause is found. The presentation usually includes pain, swelling, and dilated superficial veins. The thrombus may lead to chronic venous obstruction, or even superior vena cava syndrome. It can cause a

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pulmonary embolus. If the patient is at low risk of bleeding, a short course of thrombolytic therapy can be given. Recommended initial treatment otherwise includes full anticoagulation with unfractionated or low molecular weight heparin, followed by warfarin. If anticoagulants are contraindicated, a superior vena cava filter is a means of protection from pulmonary embolism. Elastic bandages are helpful if there is persistent swelling. If anticoagulants or thrombolytic therapy fails, surgical embolectomy can be done. Post-phlebitic syndrome 20-50% of patients with venous thrombosis develop some degree of post-phlebitic syndrome. This consists of chronic postural dependent edema and pain. It can result in venous ulceration of the ankle. Mild edema may respond to oral administration of rutosides, which are derivatives of the flavonoid rutin. They inhibit capillary permeability and fragility and are anti-inflammatory. Intermittent pneumatic compression can alleviate severe edema. Pressure gradient hose (30-40 mm gradient) for two years after an episode of venous thrombosis may prevent recurrences. Massive iliofemoral venous thrombosis (phlegmasia cerulea dolens) This syndrome causes severe swelling, cyanosis and pain in the lower extremity. It may cause shock, gangrene, pulmonary embolism or death. Predisposing factors are hypercoagulable states, trauma, surgery, malignancy, or the postpartum state. Thrombolysis should be considered. Pulmonary embolism Incidence About 600,000 episodes of pulmonary embolism occur in the United States annually, 100,000 to 200,000 of them fatal. The majority of pulmonary emboli go unrecognized. Hospitalized patients are at especially high risk. Pulmonary emboli can range from small peripheral emboli to massive obstructive lesions producing shock or cardiac arrest. The mortality rate is greater than 15% in the first 3 months after diagnosis. About 25% of cases present with sudden death. Most of the emboli arise in the lower extremities, or occasionally the pelvic veins. They rarely result from phlebitis of the upper extremity. Pathophysiology of pulmonary embolism The lungs receive blood from both the pulmonary and bronchial arteries. An embolus results in obstruction of a pulmonary artery or its branch. Vasoactive and bronchoactive agents are released from platelets, causing ventilation-perfusion mismatch. Right ventricular failure and ischemia may occur. Recognition of pulmonary embolism Dyspnea is the commonest presentation. There may be pleuritic pain, cough, or hemoptysis. Physical findings may include tachypnea and evidence of anxiety. With massive emboli, there can be hypotension shock, or cardiac arrest. Evidence of right heart failure may be present (neck vein distention, tricuspid regurgitation, accentuated pulmonic second sound). Pleurisy and hemoptysis are more characteristic of pulmonary infarction. In such cases, a pleural rub may be present. Atypical or subtle presentations are common. An underlying or coexisting disease, such as heart failure, emphysema, pneumonia or sepsis may further confuse the issue. Commonly, the only manifestation of a pulmonary embolus is worsening of the patient’s underlying condition. For example, in patients with 2

obstructive lung disease, as many as 25% of exacerbations appear to be due to pulmonary embolism in the absence of any other clinical sign and with low risk prediction by the various scoring systems. Differential diagnosis: Acute myocardial infarction Musculoskeletal disorders Costochondritis Rib fracture Pericardial disease

Aortic dissection Chest contusion Obstructive lung disease, asthma Pneumonia Pneumothorax

Laboratory: The D-dimer test is highly sensitive but not specific. It should be measured by the ELISA method. A negative test almost always excludes the diagnosis of pulmonary embolus. Troponin and BNP levels are useful for risk stratification. Elevation of these markers indicates higher risk. One should not depend on blood gases to exclude the diagnosis. Electrocardiogram: This is useful to exclude alternative diagnoses. However, the electrocardiogram is not a particularly strong diagnostic test for pulmonary embolism. It may be normal. Possible findings include new development of any of the following: Right ventricular strain pattern (T wave inversion in V1-V3) Right bundle branch block S in lead I with a Q wave and inverted T wave in lead III (“S1-Q3-T3 pattern”) ST and T wave changes, often resembling ischemia Sinus tachycardia Right axis deviation Clockwise rotation of the QRS (shift of transition zone to V5) P pulmonale Chest x-ray: This is often normal. There may be focal oligemia, a wedge-shaped peripheral opacity, or an enlarged descending right pulmonary artery. There may be cardiac enlargement, pleural effusion, atelectasis, or elevation of a hemidiaphragm. Chest CT angiography is the study of choice. It is at least as accurate as pulmonary angiography. A negative study does not always exclude a pulmonary embolus, however. (Tapson, NEJM 2008) Ventilation-perfusion scanning This can be used in patients in whom contrast dye and/or radiation should be avoided (e.g. renal insufficiency, pregnancy). If it is normal, it essentially excludes pulmonary embolism and a “high probability” scan means that the diagnosis is very likely. Unfortunately, the majority of scans are “low” or “intermediate” probability. This is of little clinical value, as a significant number of these patients do have pulmonary emboli.

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Echocardiography This not a sensitive diagnostic tool for pulmonary embolism. A hypokinetic right ventricular free wall with preserved contraction of the right ventricular apex is said to be diagnostic. There may be right ventricular dysfunction, increased right ventricular end diastolic to left ventricular end-diastolic ratio, tricuspid regurgitation, congestion and reduced inspiratory collapse of the inferior vena cava. It may be possible to visualize a right atrial or main pulmonary artery thrombus. It is very helpful in risk stratification. Right ventricular dilatation and hypokinesis, paradoxical septal motion, tricuspid regurgitation and pulmonary hypertension imply high risk. Echocardiography also aids in the differential diagnosis (myocardial infarction, cardiac tamponade, aortic dissection). Venous ultrasonography of the lower extremities This study can effectively detect or exclude the diagnosis of proximal deep venous thrombosis. Thus, it may provide supporting evidence for pulmonary embolism. Nevertheless, it is often negative even in patients with proven pulmonary embolism. Pulmonary angiography This is general regarded as the gold-standard test. However, the complication rate is 4%, with a mortality of 0.2%. It is still used in unstable patients, those with suspected pulmonary hypertension, or when an operative intervention is planned. Risk stratification Patients with normal right ventricular function and blood pressure have a good prognosis. The following factors are associated with a worse prognosis: Age > 70 troponin elevation (microinfarction) Cancer BNP elevation (shear stress) COPD chest CT -- RV:LV dimension > 0.9

heart failure right ventricular dysfunction on echo systolic blood pressure < 90

Point scoring systems can be used to determine the likelihood of a pulmonary embolus: Wells criteria: Clinical signs and symptoms of DVT 3 points Alternative diagnosis less likely 3 points Heart rate ≥ 100 1.5 points Immobilization or surgery in last 4 weeks 1.5 points Previous venous thromboembolism 1.5 points Hemoptysis 1 point Cancer 1 point Pulmonary embolus unlikely: Moderate probability: High probability

< 2 points 2-6 points >6 points

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Revised Geneva Score: Age > 65 Previous DVT or PE Surgery under general anesthesia or leg fracture within 1 month Active malignancy Unilateral leg pain Hemoptysis Heart rate 75-94 Heart rate > 94 Leg tenderness or unilateral edema

1 point 3 points 2 points 2 points 3 points 2 points 3 points 5 points 4 points

Low probability: 0-3 points Intermediate: 4-10 points High: 11 points Treatment If there is strong suspicion of pulmonary embolism, start anticoagulants while awaiting the results of definitive tests. Bed rest is advised for 24-48 hours Anticoagulation is used in all patients, unless there are major contraindications. Start with unfractionated heparin, low molecular weight heparin, or fondaparinux. Unfractionated heparin is the preferred drug when embolectomy or thrombolytic therapy is being considered, as it can be rapidly reversed. Treatment should be initiated with a weight-based bolus (e.g. 80 u/kg) followed by an infusion, usually started at 18 u/kg/hr. The activated partial thromboplastin time is maintained at 2 to 3 times the upper normal limit. This should correspond to a plasma heparin level of 0.3-0.7 IU/ml of anti-factor Xa activity. If the patient requires unusually large doses of heparin, anti-factor Xa should be used to guide. Platelet counts should be ordered daily, to permit recognition of heparin-induced thrombocytopenia. If t-PA is given, heparin is held until the activated partial thromboplastin time falls to less than twice the upper normal limit. Low molecular weight heparins are as effective as unfractionated heparin. They are given subcutaneously, using a weight-based dose. No monitoring is required, unless the patient is pregnant, has chronic kidney disease, or is massively obese (> 150 kg) or very small (< 40 kg). In the latter cases, we usually monitor the anti-Xa levels. This test is also done if the patient bleeds or has additional emboli while receiving a weight-based regimen. The usual dose for enoxaparin is 1 mg/kg every 12 hours and for dalteparin 120 u/kg every 12 hours. Fondaparinux is a third alternative that is as safe and effective as the others. It is a synthetic pentasaccharide. It is administered once daily subcutaneously. The daily dose is 5 mg for patients weighing under 50 kg, 7.5 mg for those weighing 50-100 kg., and 10 mg if the patient weighs over 100 kg. It is contraindicated in severe renal disease. It does not cause heparin-induced thrombocytopenia, unlike the heparins. Monitoring is not required.

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For cancer patients, low molecular weight heparin is safer and more effective than warfarin. The recommendation is to give it for the first 3 to 6 months, followed by warfarin. Pregnant patients run the risk of embryopathy if vitamin K antagonists are given during the first trimester. Unfractionated heparin is the usual choice during that period. Warfarin is then used for the remainder of pregnancy, except for the last few weeks. At that time heparin is resumed, so as to reduce the risk of fetal hemorrhage. Other approaches have been developed, and are still under study (see article on anticoagulant usage). Oral anticoagulation is started at the same time as heparin. Warfarin is initiated at 5 mg. daily without a loading dose. The target INR is 2 to 3. It is overlapped with heparin or fondaparinux for five days, even if the INR is in the therapeutic range before that time. Thrombolytic therapy This is used for massive or submassive pulmonary emboli when there is hemodynamic instability. Some consider the echocardiographic evidence of right ventricular dysfunction itself to be an indication, but this is controversial. The approved drug is t-PA (alteplase) 100 mg, infused over 2 hours. There is significant risk to doing this, as intracranial hemorrhage may occur in as many as 3% of cases. The patient must be carefully screened for contraindications. There is no advantage to administration of the agent directly into the pulmonary artery. Surgical embolectomy Surgery is used when thrombolytic therapy fails or is contraindicated. Additional indications include persistent right heart thrombi, paradoxical embolism, or the need for CPR due to respiratory or hemodynamic collapse. Originally, it was a very high risk procedure, but today it is performed with acceptable mortality in high-volume centers. Cardiopulmonary bypass with deep hypothermia are required. Catheter based embolectomy or fragmentation This procedure can be tried if surgery is contraindicated or if the patient is too critical to wait for thrombolytic therapy. Inferior vena cava filters These are employed if anticoagulants are contraindicated, if emboli recur during adequate anticoagulation, or if the patient undergoes surgical embolectomy. They increase the risk of deep vein thrombosis. Ambulation There is no advantage to bed rest, once the patient is fully anticoagulated. Ambulation as tolerated can be initiated at that time. _________________________________________________________________________________________ *Newer evidence reveals that there is a significant incidence of recurrent thromboembolism after stopping warfarin in patients with unprovoked venous thrombophlebitis. If there is a major risk factor (e.g. cancer) it is as high as 15% in the first year. The American College of Chest Physicians now advises indefinite anticoagulation for patients that have unprovoked proximal venous thrombosis or pulmonary embolism, provided adequate control can be achieved.

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Long-term management Duration of anticoagulation* First episode of pulmonary embolism secondary to a reversible event: at least 3 months of warfarin First episode of pulmonary embolism without identifiable cause: warfarin for 6-12 mos, possibly indefinitely Cancer patients: low molecular weight heparin for 3-6 months, then warfarin indefinitely or until cancer is resolved First episode of pulmonary embolus with thrombophilic condition: l2 months, possibly indefinitely Two or more episodes of documented pulmonary embolism: indefinite Compression stockings with a 30-40 mm gradient afford further protection. Periodic repeat venous ultrasound and d-dimer testing have been shown to be useful prognostic indicators. It has been recommended that anticoagulation be resumed if such studies are positive. Prognosis 90% resolve within 30 days with restoration of normal pulmonary hemodynamics. If the patient presents with hemodynamic impairment, the mortality is 20-30%. Clearly, the prognosis is worse if the diagnosis is missed. With adequate treatment, the mortality is about 2%. About 1.5% of patients will die in the next year. Paradoxical embolism can occur if a thrombus passes through a patent foramen ovale or other intracardiac shunt, and can result in a stroke (see article on Strokes). Chronic thromboembolic pulmonary hypertension Up to 4% of pulmonary emboli do not resolve. They organize and obstruct the pulmonary vasculature. 1015% of these patients have antiphospholipid antibody. The patient may be asymptomatic for months or years, after which he develops dyspnea, syncope and angina. Right heart failure develops, with jugular venous distention, hepatomegaly, a right ventricular heave and dependant edema. The pulmonic second sound is exaggerated and may be widely split. There may be murmurs of tricuspid regurgitation and of pulmonic regurgitation. The chest x-ray may be normal, or may show enlargement of one or both pulmonary arteries and areas of hypoperfusion or hyperperfusion. Right atrial and/or right ventricular enlargement may be present. Resting PO2 may be normal, but usually declines with exercise. The A-a gradient is usually widened. The ECG may show right atrial or right ventricular enlargement. Echocardiography reveals the pulmonary hypertension and a dilated right ventricle with reduced function. Helical CT demonstrates the thromboembolic material and helps in the differential diagnosis of pulmonary hypertension. Right heart catheterization and pulmonary angiography are the definitive studies. Coronary angiography is done if the patient is over 35.

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The treatment is surgical thromboendarterectomy, after placement of an inferior vena cava filter. Anticoagulation should be initiated after surgery. The surgical mortality is 7-24%. The postoperative course is often followed by complications, such as bleeding, reperfusion pulmonary edema, and persistent pulmonary hypertension. The survivors generally improve from NYHA Class III or IV to Class I or II. They should be maintained on vitamin K antagonists for life, with an INR of 2-3 (some recommend an INR ≥ 3 if there is antiphospholipid antibody). References Piazza G and Goldhaber SZ. Acute pulmonary embolism part I: epidemiology and diagnosis. Circulation 2006;114:28 Piazza G and Goldhaber SZ. Acute pulmonary embolism part II: treatment and prophylaxis. Circulation 2006;114:42 Stengel JW et al. Diagnostic imaging approach to pulmonary embolism. Cleveland Clinic J Med 2006;72:821 Kucher N and Goldhaber SZ. Recent advances in the diagnosis and treatment of pulmonary embolism. ACC Current Journal Review. Nov/Dec 2003 p. 28 Wells PS et al. Does This Patient Have Deep Vein Thrombosis? JAMA 2006;295:199 Fedullo PF and Tapson VF. The evaluation of suspected pulmonary embolism. New Eng J Med 2003;349:1247 Bhatia S et al. 56 year old man with progressive shortness of breath. Mayo Clin Proc;2003:491 (a case of chronic thromboembolic pulmonary hypertension) Legal G et al. Prediction of pulmonary embolism in the emergency department: the revised Geneva score. Ann Int Med 2006;144:165 Lang I. Chronic thromboembolic pulmonary hypertension – not so rare after all. New Engl J Med 2004; 350:2236 Bates SM and Ginsberg JS. Treatment of deep vein thrombosis. New Engl J Med;2004 351:268 Perlroth DJ et al. Effectiveness and cost-effectiveness of thrombolysis in submassive pulmonary embolism. Arch Int Med; 2007 167:74 Tillie-Leblond I et al. Pulmonary embolism in patients with unexplained exacerbationl of chronic obstructive pulmonary disease: prevalence and risk factors. Ann Int Med 2006; 144:390 Brüller HR et al. Antithrombotic therapy for venous thromboembolic disease. Chest 2004;126:401s-428s. Tapson VF. Medical Progress: Acute pulmonary embolism. New Engl J Med 2008; 358:1037-1052 Kearon C. Stopping anticoagulant therapy after an unprovoked venous thromboembolism. Canadian Medical Association Journal 2008;179:401-402

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