A. Risk Factors:
1. Venous stasis
a) prolonged lower extremity immobility
b) bed rest
- in one study of 100 consecutive patients in a MICU, 33% had DVT by duplex ultrasound (JAMA 1995; 274:335-7)c) surgery
d) right sided congestive heart failure
e) pregnancy (NEJM 1996;335:108-114)
(1) occurs in 1/1,000 - 1/2,000 pregnancies
(2) DVT is considerably more likely in the left leg during pregnancy (Thromb Haemost 1992; 67:519-20). Of pregnant women developing venous thromboembolism, 40% occur in the first trimester, 18% occur in the second trimester, and 42% occur in the third trimester (Thromb Haemost 2007; 97:186-90)
(3) risk of DVT is 5X higher in pregnant women than controls
(4) in the third trimester of pregnancy, the pO2 is about 15 mm lower in the supine position rather than the upright position so ABGs should always be assessed upright if possible when evaluating the pregnant patient for pulmonary embolism
(5) patients known to have protein C or protein S deficiency have an 8-fold increase in pregnancy-associated thromboembolism, mainly in the post-partum period; prophylactic anticoagulation of these women may be warrented in the third trimester and in the post-partum period (Ann Intern Med 1996; 125:955-960)
2. Endothelial injury
a) previous DVT(1) risk of recurrent DVT is 17.5% in 2 years (Ann Intern Med 1996; 125:1-7)
(2) highest risk is in patients with malignancy and hypercoaguable states
b) femoral intravenous cathethers
(1) associated with DVT in 25% of patients in one study (Critical Care Medicine1995; 23:52-9)
c) trauma & lower extremity surgery (eg. hip surgery)
(1) calf vein thrombosis:
(a) 40-60% of patients with hip prothesis
(b) 60-70% of patients with knee prothesis
(c) 58% of patients with major trauma (N Engl J Med 1994; 331:1601-6)
(2) proximal DVT
(a) 20% in either hip or knee prothesis
(b) 18% of patients with major trauma (N Engl J Med 1994; 331:1601-6)
d) strenuous muscle activity
(1) primarily a risk for upper extremity DVT
(a) in patients with isolated upper extremity DVT, inherited hypercoaguability is rarely present (Ann Intern Med 1997; 126:707-11)
3. Hypercoagulability (Ann Intern Med 2003; 138:128-34)
a) Primary (inherited) hypercoaguable states
(1) Factor V Leiden mutation
(a) caused by a mutation in the factor V gene (factor V Leiden mutation) resulting in a resistance of factor V to activated protein C (protein C works by lysing factors Va and VIIIa)
i) this mutation appears to have originated in European populations and the incidence in racial groups varies considerably (JAMA 1997; 277:1305-7):
(1) Caucasian Americans - 5.27%
(2) Hispanic Americans - 2.21%
(3) Native Americans - 1.25%
(4) African Americans - 1.23%
(5) Asian Americans - 0.45%
ii) The risk of clotting depends on the number of abnormal genes. Homozygous individuals are at extremely high risk of life-threatening thrombosis (approximately 80-fold increased risk). Most homozygous individuals will experience at least 1 thrombotic event in their lifetime (Blood 1995; 85:1504-8). The average age of thrombosis in homozygotes = 31 years. Heterozygous individuals are at about 5-10 fold increased risk of thrombosis. Average age of onset of thrombosis in heterozygotes = 44. The incidence of thrombosis increases exponentially with age and factor V Leiden mutation should be considered in both young individuals who clot as well as elderly individuals who clot (Ann Intern Med 1997; 126:528-531)
(b) Women are at particularly high risk of thrombotic complications of factor V Leiden. Women who use oral contraceptives are at extremely high risk of thrombosis (about 30-fold increase) if they are heterozygous for the factor V Leiden mutation (Lancet 1994; 344:1453-7). There is a strong association with factor V leiden and pregnancy-associated DVT/PE - in a study of 407 obstetric patients, the incidence of pregnancy-associated thromboembolism in patients carrying the factor V Leiden gene was 28% whereas the incidence of thromboembolism in non-carriers was <1% (Am J Obstet Gynecol 1997;176:883-6, 1997); in another study, 43% of all pregnancy-associated thrombosis was attributable to factor V Leiden (N Engl J Med 2000; 342:374-80)
(c) Factor V Leiden is the most common inherited cause of hypercoaguability (about 10 times more frequent than the other inherited hypercoaguable states. The incidence in any population of patients depends on the racial and genetic distribution of that population but in general, it accounts for about 20-40% of all DVT/PE.
(d) Factor V Leiden can be diagnosed by genetic testing using PCR (polymerase chain reaction) which indicates whether the individual is heterozygous (or homozygous) for the factor V Leiden mutation (performed in the molecular pathology laboratory)
(e) Screening for factor V Leiden may be useful in certain situations. Family members should be offered genetic counseling with screening for the gene and appropriate counseling regarding risk avoidence and DVT prophylaxis (ie, during surgery, etc.). Empiric anticoagulation of asymptomatic family members carring the gene is not warrented. Screening the general population does not appear cost effective at the present time.
(2) Hyperhomocysteinemia
(a) High plasma homocysteine levels are a risk for DVT (NEJM 1996; 334:759-62) and can be caused by genetic abnormalities (cystathionine B-synthetase and 5,10-methylenetetrahydrofolate reductase) drugs (methotrexate, phenytoin, theophylline, and carbamazepine) and medical conditions (renal insufficiency, poor nutrition, hypothyroidism, cancer, and diets high in animal fat
(b) Diagnosis is by fasting serum homocysteine level. However, 40% of patients with hyperhomocysteinemia will be missed and require serum homocysteine levels before and after oral methionine loading
(c) Treatment with folic acid 3-5 mg/day, B6 50 mg/day, and B12 100 mg/day can reduce homocysteine levels. However, reducing homocysteine levels does not reduce the risk of subsequent venous thromboembolism (Ann Inter Med 2007; 146:761-7).
(3) Prothrombin G-A20210 gene variant
(a) Genetic variant which results in increased levels of prothrombin and in hypercoaguability and accounts for approximately 14% of all patients with DVT/PE. Heterozytotes have increased risk of DVT by about 3-fold and homozygotes have extremely high incidence of thrombosis (all patients in some studies). The combination of heterozyous state for both factor V Leiden and prothrombin G-A20210 gene variant also gives extremely high probability of thrombosis and such patients may be candidates for life long anticoagulation
(b) Diagnosis is by genetic testing. The condition has similar implications for genetic counseling as Factor V Leiden.
(4) Protein C deficiency
(a) Heterozygote prevalence is about 1:200 - 1:300. Patients with thrombosis and protein C deficiency will have levels around 50% of normal. Coumadin can affect protein C levels so laboratory tests should be performed once the patient is off of coumadin.
(5) Protein S deficiency
(a) Heterozygous state incidence is about 1-2% of the population. Patients with thrombosis and protein S deficiency will have levels around 50-70% of normal. Coumadin will also falsely lower protein S levels.
(6) Antithrombin III deficiency
(a) patients with thrombosis and anti-thrombin III deficieny will have levels less than 70 or 80% of normal
(7) Miscellaneous inherited risks: elevated levels of factor XI (confers a 2-fold increased risk), hypoplasminogenemia, dysplasminogenemia, tissue plasminogen activator release deficiency, increased levels of plasminogen activator inhibitor, dysfibrinogenemia, heparin cofactor II deficiency, fibrinolytic abnormalities, elevated levels of factor VIII, elevated levels of factor IX
b) Secondary hypercoaguable states:
(1) Anti-phospholipid antibody. This syndrome can occur as a primary condition, however, many diseases can also cause anti-phospholipid antibodies including: systemic lupus erythematosus (50% of patients), rheumatoid arthritis, Sjogren's syndrome, systemic sclerosis, ankylosing spondylitis, HIV, syphilis, and Lyme disease. Additionally, a number of drugs can induce anti-phospholipid antibodies including: phenothiazines, procainamide, hydralazine, phenytoin, and oral contraceptives.
(2) Certain malignancies. Malignancy will be diagnosed at the initial hospitalization of DVT/PE in 12% of patients (Ann Intern Med 1996; 125:785-93). The most common primary malignancies associated with DVT/PE are hematologic malignancies followed by lung cancer and gastrointestinal cancer (JAMA 2005; 293:715-22); however, many malignancies can result in hypercoaguability. Extensive searches for occult cancer is not warrented but routine age and gender appropriate cancer screening should be undertaken.
(3) Heparin-induced thrombocytopenia (HIT). Caused by an antibody directed against the heparin-platelet factor 4 complex which binds to Fc receptors on platelet surfaces (Blood 1994; 83:3232-9) and occur in 3-4% of patients receiving unfractionated heparin for 7-10 days. It is extremely unlikely with factor Xa inhibitors such as fondaparinux. HIT usually causes platelets to fall < 100,000 (as opposed to > 100,000 in non-immune heparin associated thrombocytopenia) and usually occurs 5-14 days after starting heparin in patients who have not previously received heparin (as opposed to 0-4 days for non-immune heparin-associated thrombocytopenia). HIT is associated with about a 50% incidence of subsequent thrombosis (usually venous) as opposed to non-immune heparin-associated thrombocytopenia which is benign
(5) Estrogen therapy. In one study of 2763 postmenopausal women randomly given conjugated estrogen or placebo, estrogen was associated with a 3-fold increased risk (Ann Intern Med 2000; 132:689-96). In a second study, the risk of venous thromboembolism was increased 9.6-fold in women using estrogens (Lancet 2000; 355:2088-90). The risk of estrogens was even higher in women with lower extremity fractures, cancer, surgery, or non-surgical hospitalization
(4) Miscellaneous. Hypertension, obesity, and cigarette smoking were identified to be associated with pulmonary embolism in women in the Nurses' Health Study (JAMA 1997; 277:642-5) and smoking and obesity conferred a 2.5 fold risk for DVT/PE (Am J Med 2005; 118:978-80). Other risks include: polycythemia vera & other myeloproliferative diseases, paroxysmal nocturnal hemoglobinuria, nephrotic syndrome, vasculitis, increased factor VII and fibrinogen levels, and certain anti-cancer drugs. Venous thromboembolism occured in 10% of patients with Wegener's granulomatosus in one study (Ann Intern Med 2005; 142:620-6)
B. Diagnosis:
1. Clinical:
a) Very inaccurate (about 50%). Frequent historical findings include: pain, swelling, and erythema. Frequent physical findings include: Homan's sign (present in 22% patients with DVT & 28% of patients without DVT) and a palpable cord (present in 30% patients with DVT & 27% of patients without DVT). Of note, many patients will have no symptoms and a normal physical exam.
2. Duplex ultrasonography:
a) 91% sensitive; 99% specific considering all DVT; the sensitivity approaches 100% for femoral DVT. It is less able to detect isolated calf or iliac vein thrombosis
b) For outpatients with suspected DVT, it is safe to withhold anticoagulation if an initial duplex ultrasound and a second duplex in 5-7 days are both negative (Ann Intern Med 1998; 128:1-7).
c) A positive duplex scan justifies treatment and does not require confirmation with venography. Duplex ultrasound should always be done in both legs with suspected DVT because of the high incidence of assymptomatic DVT in the contralateral leg (even when the ipsilateral leg has no DVT by duplex ultrasound).
3. Venography:
a) Although it is generally considered to be the "gold standard" in clinical trials, it is rarely used clinically since the development of duplex ultrasound.
4. Helical leg CT:
a) Leg CT can be performed as a primary test or combined with helical chest CT. In the PIOPED II study, leg CT was able to detect some cases of thromboembolism not visible on chest CT and the authors recommended that thigh CT be combined with chest CT. It should not be done routinely in patients under age 40 or in pregnant women because of the risk of genital and fetal radiation. The PIOPED II study also determined that CT venography is diagnostically equivilent to ultrasound in the diagnosis of DVT (AJR 2007: 189: 1071-6)
C. Treatment:
Large vessel lower extremenity DVT should be treated similarly to pulmonary embolism; see treatment of PE below.
Calf Vein Thrombosis warrents special mention. 20% will propagate up the thigh to cause iliofemoral DVT and therefore recommendations are to treat with heparin/coumadin like other DVTs. If anticoagulation risky, an alternative is to follow the patient with serial duplex scans.
Superficial vein thrombosis does not require treatment with anticoagulants but duplex ultrasonography should be performed to exclude concurrent calf vein thrombosis.
Upper extremity DVTs should be treated with heparin and coumadin similarly to lower extremenity DVT (Chest 2004;126:401S-428S)
Pulmonary Thromboembolism (N Engl J Med 2008; 358:1037)
A. Background:
Approximately 1.5 million patients per year in U.S. have DVT - about 30% will have symptomatic and an additional 30% will have asymptomatic PE. PE accounts for about 300,000 deaths in the United States per year. If PE recognized and treated: the mortality is 2%, however, if PE unrecognized and not treated: the mortality is 25%. PE accounts for 15% of post-operative deaths and 10-20% of all in-hospital deaths. 20% of patients with PE will die of other medical conditions within 1 year of the diagnosis of PE with cancer and infection the most common causes of death.
B. Diagnosis:
1. Clinical presentation:
a) Many PEs are asymptomatic; in one study, 40% of patients with DVT had asymptomatic PE. If symptomatic, most frequent symptoms are: chest pain (88%), dyspnea (84%), cough (53%), hemoptysis (30%)
b) The physical exam is also non-specific. Tachypnea and tachycardia are most common with 92% of patients having a respiratory rate greater than 14. Fever occurs in 18-50%. In the PIOPED study, 97% of patients with PE had at least one of: pleuritic chest pain, dyspnea, or respiratory rate greater than 20/min. Of note, the chest pain of pulmonary embolism is equally likely to be reproduced by chest palpation as not and so reproduction of the pain with palpation does not exclude pulmonary embolism (BJM 2005; 330:452-3)
c) The probability of PE can be estimated by Well's criteria which assigns points for different clinical findings. Less than 2 points indicates low probability, 2-6 points indicates intermediate probability, and greater than 6 points indicates high probability (Thromb Haemost. 2000;83:416-20).
3.0 - Signs of DVT
1.5 - HR greater than 100
1.5 - Immobilization for more than 3 days or surgery in past 4 months
1.5 - Previous PE
1.0 - Hemoptysis
1.0 - Malignancy
3.0 - PE as or more likely than other diagnoses2. Chest x-ray:
a) The plain chest x-ray is often normal, especially in the acute phase. When abnormalities are seen the most common findings are: cardiomegaly(the most common acute chest x-ray abnormality), enlargement of main pulmonary artery (normal right PA = 16 mm in men and 15 mm in women), elevated hemidiaphragm, pulmonary opacities, Hampton's hump (3-5 cm opacity usually on right hemidiaphram), atelectasis (usually 1-3 cm above diaphragm; horizontal, linear, and several cm long), cavitation (suggests pulmonary infarction or septic embolus), and pleural effusions.
3. Plasma D-dimer levels:
a) In a study of 566 patients with suspected DVT/PE, a negative D-dimer was effective in excluding DVT/PE if the clinical suspicion was low (Ann Intern Med 2006; 144:812-21).
b) D-dimers are primarily useful in outpatients and in ER patients and are generally not used in hospitalized patients due to the high incidence of false positives in these patients.
c) The D-dimer is useful as an adjunct to other diagnostic testing but is generally not a sufficient test to diagnose pulmonary embolism by itself.
d) D-dimer levels appear to correlate with overall inpatient mortality in patients with pulmonary embolism and levels over 5,000 ng/ml are associated with a 3-fold increase in mortality (Crit Care Med 2007; 35:1937-41).
4. Troponin I levels
a) Although not diagnostic of pulmonary embolism, elevated troponin I levels are associated with a higher risk of death (Circulation 2007; 116:427-33)
5. Arterial blood gases
a) A-a gradient increased in 95% of patients with proven PE. A-a gradient = [150 - (5/4 x pCO2)] - pO2. normal = 4 + (age ÷ 4).
6. Ventilation/perfusion scan
a) Normal: perfusion is normal. Low probability: small V/Q mismatches, focal V/Q matches without x-ray abnormalities, or perfusion defects much smaller than x-ray abnormalities. Intermediate probability (indeterminate): diffuse severe airway obstruction, matched V/Q and x-ray abnormalities, or single segmental V/Q mismatch. High probability: perfusion defects much larger than x-ray abnormalities or 2 or more segmental V/Q mismatches.
b) Ventilation defects can accompany pulmonary arterial embolization for up to 48 hours.
c) Patients with COPD pose problems because of the increased chance of indeterminate scans (60% of patients) and they are less likely to have normal (5% of patients) or high probability (5% of patients) scans compared to patients without cardiopulmonary disease. However, a high probability V/Q scan or a normal V/Q scan has the same predictive value in patients with COPD as in those without COPD
d) Predictive value: A normal study excludes pulmonary embolism. All other findings must be taken in the context of the clinical suspicion of pulmonary embolism. The key study examining the clinical utility of the V/Q scan was the PIOPED study (Prospective Investigation Of Pulmonary Embolism Diagnosis) published in 1990 (JAMA 1990; 263:2753-9). In this study, patients underwent both V/Q scans as well as pulmonary angiograms and to determine how well V/Q scans correctly identified patients with pulmonary emboli.
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(1) a normal V/Q scan effectively excludes clinically significant PE (Ann Int Med 1991; 114:300-6)
(2) a high probability V/Q scan plus high clinical suspicion justifies treatment without an angiogram
(3) a low probability V/Q scan plus low clinical suspicion justifies no treatment without an angiogram
(4) any other combination of V/Q scan probability and clinical suspicion requires further evaluation with either a duplex scan or a pulmonary angiogram
7. Duplex ultrasound of the legs
In patients suspected of having PE, only 29% of duplex ultrasounds will be abnormal at the time of presentation. It has been hypothesized that the clots in the deep veins of the legs have dislodged in patients with PE and thus are not present for identification by duplex ultrasound of the legs.
8. Helical CT
a) The utility of the CT-pulmonary angiogram is dependent on several factors:
(1) The quality of the scanner; multi-channel CT machines are optimal
(2) The expertise of the radiology technician performing the test (including patient instruction for breath-holding and timing of the IV contrast dye bolus).
(3) The experience of the radiologist performing the study.
(4) The population of patient being studied. The best quality studies come from studies of otherwise relatively healthy patients with relatively normal chest x-rays (such as emergency department patients); in these patient populations the sensitivity for detecting pulmonary embolus is good (70%) and specificity very good (19%) in one recent study (Intensive Care Med 2001; 27:1481-6). However, in critically ill patients, the sensitivity is only 55% although the specificity is still good at 90% (Arch Surg 2001; 136:505-11); this may relate to the higher incidence of other pulmonary abnormalities in critically ill patients such as atelectasis and pulmonary infiltrates. Obesity also reduces the sensitivity of CT pulmonary angiography.
(5) The location of the pulmonary embolus. CT is best for proximal, main pulmonary artery clot but less accurate for segmental and subsegmental clot where it can be difficult to distinguish clot from lymph nodes, atelectasis, and mucus plugs.
b) The CT scan results are most useful when taken in the context of the physician's clinical assessment of the probability of pulmonary embolus. The PIOPED II study examined the efficacy of the CT pulmonary angiogram for detecting pulmonary embolus in 824 patients (N Engl J Med 2006; 354:2317-27). This study used Well's criteria combined with the CT pulmonary angiogram results. Patients over 40 who were not pregnant also underwent simultaneous CT femoral venogram. Overall, the sensitivity of CT pulmonary angiogram alone was 83% and the specificity was 96%. The sensitivity of CT pulmonary angiogram OR venogram was 90% and the specificity was 95%. The following table indicates the percentage of patients in each group who actually had PE/DVT (as diagnosed by alternative methods including duplux ultrasound and pulmonary angiogram):
High Clinical Suspicion Intermediate Clinical Suspicion Low Clinical Suspicion CT Positive
96% 90% 57% CT Negative
18% 8% 3% c) a major advantage of helical CT over ventilation-perfusion scanning is the ability to diagose other lung diseases, especially in patients with pre-existing cardiopulmonary disease
d) personal recommendations for current use:
(1) if you are at an institution where there there is a recent generation multi-channel CT scan, where there are technicians who are experienced with the correct technique, and there are radiologists experienced in interpreting the scans, CT can be used as a first line test in lieu of V/Q scans
(2) if you are at an institution where there are EITHER there is an older generation CT scanner OR technicians who are not experienced in the proper technique OR radiologist lacking experience in interpreting the scans, V/Q is still the initial test of choice.
(3) if the clinical suspicion is high or intermediate, a negative helical CT does not exclude PE. In this situation, a second study (usually D-dimer and a duplex ultrasound of the legs) should be performed and if indeterminate, then a pulmonary angiogram should be performed as a follow up test since false negative helical CT studies are common in this population.
(4) if the clinical suspician is low, and the helical CT is positive, confirmation of PE with an alternative method (such as pulmonary angiogram) may be desirable since false positives studies can occur
(5) if the helical CT is "indeterminate" (usually becuase of improper dye injection timing or artifact), then additional tests are required (usually a pulmonary angiogram)
(6) if the patient has significant underlying lung disease and a baseline abnormal chest x-ray, then helical CT is generally preferable to V/Q scans as an initial technique since there is a high likelihood that V/Q will be "indeterminate" and require the patient to undergo additional testing to diagnose or rule out PE
(7) if the patient is at risk of dye injury (IV contrast dye allergy or renal insufficiency), then V/Q may be a better first study to avoid the large bolus of dye associated with helical CT, especially if a pulmonary angiogram becomes subsequently necessary. Young patients with a normal chest x-ray are also good candidates for V/Q scans since if the scan is normal, no additional testing is necessary and pulmonary embolism can be confidently excluded. Because most CT-PA algorithms are based on injection of IV contrast dye through an anticubital vein, in patients in whom an anticubital IV cannot be established, a V/Q scan may be preferable to a CT-PA.
9. Magnetic resonance angiography
MRI is currently considered experimental for pulmonary embolism but offers the promise of future use. A significant advantage is the abililty to avoid iodinated contrast dye in patients wtih renal insufficieny and dye allergy. Initial studies indicate that the sensitivity and specificity are probably eqivilent to CT. The PIOPED III study will examine the role of MRI in PE in the future.
10. Angiography
a) complication rate = 1.6% (0.3% mortality - mainly in critically ill patients).
b) gold standard but increasingly less frequently performed due to the widespread availability of CT.
c) false positives have been reported in: malignancy, sarcoid, Takayasu's arteritis, and angiosarcoma
C. Treatment (Chest 2004;126 supplement):
1. Heparinization strategies (Chest. 2004;126:188S-203S):
a) heparin should be begun when diagnosis is suspected, not when diagnosis is proven
b) heparin does not cross the placenta and is safe during pregnancy
c) contraindicated in: intracranial bleeding, intracranial lesions prone to bleeding, active internal bleeding, heparin-induced thrombocytopenia.
d) there is no need to put patients with DVT on bedrest after heparin is started; patients may ambulate normally (Semin Vasc Surg 2005; 18:148-52)
e) treatment regimens:
(1) continuous intravenous infusion:
(a) adjust dose to achieve PTT = 1.5 - 2.5 times control
(b) check PTT Q6 hr. until PTT is between 60 and 105 then check PTT QD; check PTT 6 hours after any dose change
(c) heparin drip adjustment based on patient's weight; mix 25,00 units heparin in 250 ml D5W
- initial dose: 80 units/kg then 16 units/kg/hour
- PTT < 45: additional 80 units/kg rebolus then increase drip by 3 units/kg/hour
- PTT 45-59: additional 40 units/kg rebolus than increase drip by 1 units/kg/hour
- PTT 60-105: no change
- PTT 106-125: decrease drip by 2 units/kg/hour
- PTT 126-180: hold infusion for 1 hour, then decrease drip by 3 units/kg/hour
- PTT >180: hold infusion until dosing re-evaluated by physician
(d) check platelet count at least every other day through day 14 of heparin therapy and stop heparin if the platelet count falls below 100,000
(e) continue heparin for minimum of 5 days (NEJM 1990; 322:1260-4) and the INR is therapeutic
(2) Low molecular weight heparin
(a) Background: low molecular weight heparin offers longer half life, less hemorrhagic complications, greater ease of administration (once or twice per day subcutaneously) than unfractionated heparin (Chest 2005; 128:2203-10). The incidence of heparin-induced thrombocytopenia is similar in patients receiving unfractionated heparin and low molecular weight heparin (Chest 2007; 132:1108-10).
1) Enoxaparin (1 mg/kg SQ BID) given at home was equally effective as standard heparin given IV in the hospital for management of acute DVT (N Engl J Med 1996; 334:677-81)
2) Enoxaparin 1.5 mg/kg SQ QD was equally effective as enoxaparin 1.0 mg/kg SQ BID or unfractionated heparin IV in 900 patients with DVT, including 273 with PE (Ann Intern Med 2001; 134:191-202)
(b) Current FDA-approved indications:
1) For inpatient treatment of DVT or PE
- enoxaparin 1 mg/kg SQ BID
- enoxaparin 1.5 mg/kg SQ QD
- tinzaparin 175 u/kg SQ QD
2) For outpatient treatment of DVT
- enoxaparin 1 mg/kg SQ BID
- tinzaparin 175 u/kg SQ QD
(a) Precautions in use: the half life can be prolonged in renal insufficiency and should be used with precaution in patients with creatinine clearance below 30 ml/min (Curr Opin Pulm Med 2007; 13:409-13) . Bleeding can occur in obese patients (body mass index greater than 50) in whom correct dosing can be difficult to estimate.
2. Coumadin strategies (Chest. 2004;126:204S-233S):
a) Contraindications: as per heparin; additionally, coumadin contraindicated during pregnancy since in the first trimester, coumadin causes congenital abnormalities
b) Begin same day heparin is begun
c) Start with 10 mg/day for days #1 & #2, then administer at estimated daily dose (Ann Intern Med. 2003;138:714-719)
(1) check INR QD until stable and adjust to achieve INR of 2.0 - 3.0
(2) the INR must be checked frequently (every 1-2 weeks) while patients are receiving coumadin
(3) need minimum of 4 - 5 days overlap with heparin
d) Patients must be cautioned about common foods and drugs which can alter coumadin's effect (often dramatically!)
e) The duration of anti-coagulation is dependent on the patient population (Chest. 2004;126:401S-428S):
(1) First DVT/PE and reversible causes of clotting: 3 months
(2) First DVT/PE and idiopathic: 6-12 months and consider indefinite anticoagulation
(3) DVT/PE and 1 cause of hypercoagulability: 6-12 months and consider indefinite anticoagulation
(4) DVT/PE and anti-phospholipid antibody syndrome OR 2 combined causes of hypercoaguability: 12 months and consider indefinite therapy
(5) DVT/PE and cancer: low molecular weight heparin for 3-6 months and then coumadin until the cancer resoloves (because many patients with cancer will clot despite therapeutic doses of coumadin).
(6) Two or more DVT/PE: indefinite therapy.
f) Certain factors predict patients more likely to develop re-thrombosis:
(1) Elevated D-dimer 1 month after discontinuing coumadin (N Engl J Med 2006; 355:1780-9)
(2) Residual thrombus seen on a post-treatment duplex ultrasound indicates a higher risk of recurrent venous thromboembolism (Ann Intern Med 2002; 137:955-60).
3. Treatment of heparin-induced thrombocytopenia
(a) lepirudin (Refludan)
- inhibits free and clot bound thrombin
- 0.4 mg/kg (up to a maximum of 110 kg) IV over 20 seconds
- 0.15 mg/kg/hr (up to a maximum of 110 kg) x 2-10 days
- keep PTT 1.5-2.5 normal
- adjust dose for renal failure
(b) Argatroban
- thrombin inhibitor
- 2 ug/kg/min continuous infusion
- keep PTT 1.5 - 3.0 times normal
- adjust dose for hepatic failure (no dosage necessary for renal impairment)
4. Factor X inhibitors
Idraparinux is an alternative to coumadin and requires no laboratory monitoring. It can be given as a weekly subcutaneous injection. In a study of 2,904 patients with DVT and 2,215 patients with PE treated with either idraparinux or coumadin, patients with DVT had equal recurrence rates (2.9% v. 3.0%) but patients with PE had a recurrence rate of 3.4% with idraparinux v. 1.6% with coumadin (N Engl J Med 2007; 357:1094-104). At present, idraparinux is not approved by the FDA for use in the United States.
Rivaroxaban is an oral alternative to coumadin and requires no laboratory monitoring. A phase II study indicates promise in venous thromboembolism (Circulation 2007; 116:131-3)
5. Thrombolytic strategies (Chest. 2004;126:401S-428S):
(a) Background: Thrombolytics are associated with a 6.3% major bleeding risk and a 1.2% cerebral hemorrhage risk (Chest 1999; 115:1695-1707). On the other hand, the mortality of pulmonary embolus falls from 25% in untreated patients to 2% in heparin-treated patients. Therefore, a prudent goal would be to only treat the patients who are likely to die of pulmonary embolism so as to not subject those who would survive with heparin alone to the risks of thrombolysis. The difficulty is identifying those patients at the highest risk of death. A recent meta-analysis failed to determine if thrombolytics are better than heparin based on the quality of available clinical trials (Cochran Database Syst Rev 2006:CD004437). At present, the best available data indicates that these patients are those with:
- respiratory failure
- shock
- possibly with right ventricular dysfunction by cardiac echo and/or patients with high levels of troponin I or brain natriuretic peptide (BNP). In a study of 1.416 patients with pulmonary embolism, an echocardiographic RV/LV ratio greater than or equal to 0.9 was associated with a 6.6% mortality rate as opposed to patients who had a ratio less than 0.9 who had a 1.9% mortality rate (Chest 2008; 133:358-62). In a meta analysis of 20 published studies, an elevated troponin was associated with a 19.7% mortality rate whereas a normal troponin level was associated with a 3.7% mortality rate (Circulation 2007; 116:427-33). The RV to LV ratio on CT scan has been proposed as a marker for more massive pulmonary embolism but has not yet been subject to clinical study.
- possibly in massive ileo-femoral thrombosis
(b) contraindications:
(1) absolute:
a) active internal bleeding
b) CVA, intracranial surgery, or intraspinal surgery within the past 2 months
c) intracranial neoplasm
(2) relative (major):
a) surgery, obstetrical delivery, organ biopsy, or puncture of non-compressible vessel within the previous 10 days
(b) trauma, GI bleeding, or CPR within the previous 10 days
c) cerebrovascular disease
d) severe uncontrolled hypertension
(3) relative (minor):
a) recent minor trauma
b) diabetic hemorrhagic retinopathy
c) probable left ventricular or left atrial thrombus
d) coagulopathy
e) pregnancy
(f) septic thrombophlebitis
g) endocarditis
h) age > 75
(c) Treatment: tissue plasminogen activator (t-PA), 100 mg IV over 2 hours. Begin heparin immediately following the end of t-PA infusion (without loading dose)
6. Inferior venal caval filters (N Engl J Med 1998; 338:409-16)
(a) Indications: anticoagulants contraindicated, PE despite anticoagulants, complications arising from anticoagulants
(b) Complications: migration, occlusion, caval perforation, development of collateral venous flow (thus permitting recurrent PE).
(c) A new type of removable filter now exists. These filters can be placed temporarily but must be either repositioned or removed at 10 days. These devices can give protection during a period of time when anticoagulation is temporarily contraindicated. In one recent study, only 1/3 of the temporary filters were actually removed, however (Am J Surg 2005; 190:858-63)
5. Emergency surgical embolectomy and angiographic catheter fragmentation/extraction:
Both of these techniques should be reserved for angiographically-proven massive PE with hemodynamic compromise, with the availability of experienced thoracic surgical team, and there has been failure of or contraindication to pharmacologic thrombolysis. Both techniques pose additional risk and are associated with high mortality rates. A recent review of surgical embolectomy for PE indicates an over-all mortality of 20-30% (Am J Cardiol 2007; 99:421-3)
D. Prophylaxis (Chest. 2004;126:338S-400S):
a) general surgery patients:
(1) low risk, minor general surgery patients < 40 years: none
(2) moderate risk general surgery patients and those 40-60 years: SQ heparin 5,000 units BID or low molecular weight heparin
(3) high risk general surgery patients and those over age 60: SQ heparin 5,000 units TID or low molecular weight heparin (intermittent pneumatic compression if patient is prone to wound hematoma formation with low dose heparin)
(4) very high risk general surgery patients: low dose SQ heparin (or low molecular weight heparin) + intermittent pneumatic compression or graduated compression stockings
(5) very high risk surgery patients such as those undergoing cancer surgery should be considered for post-hospital low molecular weight heparin
(6) patients at high risk for bleeding: intermittent pneumatic compression or graduated compression stockings
b) gynecologic surgery patients:
(1) brief procedures for benign disease - early ambulation only
(2) laparoscopic procedures plus other clotting risks: low dose unfractionated heparin, low molecular weight heparin, intermittent pneumatic compression or graduated compression stockings
(3) major procedures for benign disease: SQ heparin 5,000 units BID
(4) extensive procedures for malignancy: SQ heparin 5,000 units TID or low molecular weight heparin
(5) extensive procedures for malignancy in patients over 60 years old - continue prophylaxis for 2-4 weeks after discharge
c) urologic surgery:
(1) TURP and other low risk procedures: early ambulation only
(2) major open procedures: SQ heparin 5,000 units BID or TID; elastic stockings, intermittant pneumatic compression, or low molecular weight heparin are acceptable alternatives
(3) highest risk patients: elastic stockings and/or intermittant pneuatic compression plus either low dose SQ heparin or low molecular weight heparin
d) orthopedic surgery:
(1) total hip replacement: low molecular weight heparin, fondaparinux, or coumadin (dosed to keep the INR 2.0 - 3.0)
(2) hip fracture patients: low molecular weight heparin, fondaparinux, or coumadin (dosed to keep the INR 2.0 - 3.0)
(3) total knee replacement surgery: low molecular weight heparin, fondaparinux, or coumadin (dosed to keep the INR 2.0 - 3.0)
e) multiple trauma patients:
(a) low molecular weight heparin
(b) intermittant pneumatic compression devices if low molecular weight heparin is contraindicated
(c) screening duplex ultrasound if inadequate prophylaxis given; IVC filter only if duplex ultrasound is positive
(d) continue prophylaxis post-hospital discharge if mobility is impaired
f) intracranial neurosurgical patients: intermittent pneumatic compression with or without elastic stockings (low molecular weight heparin or low dose SQ heparin are alternatives)
g) acute spinal cord injury with paralysis patients: low molecular weight heparin
h) medical patients:
(a) congestive heart failure, severe respiratory disease, or confined to bed with one or more risk factors: low dose SQ heparin or IV heparin
(b) critical care: low dose SQ heparin or IV heparin (graduated compression stockings or intermittant pneumatic compression devices if high risk of bleeding exists)
i) long distance travel:
(a) for most travellers: avoid tight fitting clothing, avoid dehydration, stretch calf muscles frequently
(b) for high risk travellers, graduated compression stockings or a single dose of low molecular weight heparin
j) drug dosing:
(1) SQ heparin: 5,000 u BID or TID
(2) enoxaparin: 30 mg BID or 40 mg QD
(3) dalteparin: 2,500 to 5,000 u QD
(4) tinzaparin: 75 u/kg QD
(5) nadroparin: 2,850 u QD
last updated 3/11/08