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Author: Donald Schreiber, MD, CM, Assistant Professor of Surgery, Stanford University School of Medicine; Research Director, Division of Emergency Medicine, Stanford University Hospital
Donald Schreiber, MD, CM, is a member of the following medical societies: American College of Emergency Physicians
Editor(s): Francis Counselman, MD, Program Director, Chair, Professor, Department of Emergency Medicine, Eastern Virginia Medical School; Francisco Talavera, PharmD, PhD, Senior Pharmacy Editor, Pharmacy, eMedicine; Gary Setnik, MD, Chair, Department of Emergency Medicine, Mount Auburn Hospital; Assistant Professor, Division of Emergency Medicine, Harvard Medical School; John Halamka, MD, Chief Information Officer, CareGroup Healthcare System, Assistant Professor of Medicine, Department of Emergency Medicine, Beth Israel Deaconess Medical Center; Assistant Professor of Medicine, Harvard Medical School; and Barry Brenner, MD, PhD, Chairman, Department of Emergency of Medicine, Professor, Departments of Emergency Medicine and Internal Medicine, University of Arkansas for Medical Sciences INTRODUCTION Section 2 of 10 Author Information Introduction Clinical Differentials Workup Treatment Medication Follow-up Miscellaneous Bibliography
Background: Deep venous thrombosis (DVT) and its sequela, pulmonary embolism, is the leading cause of preventable in-hospital mortality in the US. Although pulmonary embolism is discussed elsewhere in this text, it must be emphasized that it is primarily a complication of DVT.
The first reference to peripheral venous disease is recorded on the Ebers papyrus in 1550 BC, which documents the potential fatal hemorrhage that may ensue from surgery on varicose veins. In 1644, Schenk first observed venous thrombosis when he described an occlusion in the inferior vena cava. In 1846, Virchow recognized the association between venous thrombosis in the legs and pulmonary embolism. Heparin only was introduced to clinical practice in 1937. Over the last 25 years, considerable progress has been made in the pathophysiology, diagnosis, and treatment of DVT.
Pathophysiology: Virchow triad as first formulated (venous stasis, vessel wall injury, and a hypercoagulable state) is still the primary mechanism for the development of venous thrombosis. The relative importance of each factor still is debated. The formation, propagation, and dissolution of venous thrombi represent a balance between thrombogenesis and the body's protective mechanisms, specifically the circulating inhibitors of coagulation and the
In practical terms, the development of venous thrombosis is best understood as the activation of coagulation in areas of reduced blood flow. This explains why the most successful prophylactic regimens are anticoagulation and minimizing venous stasis. DVT of the lower extremity usually begins in the deep veins of the calf around the valve cusps or within the soleal plexus. A minority of cases arise primarily in the ileofemoral system as a result of direct vessel wall injury, as seen with hip surgery or catheter-induced DVT. The vast majority of calf vein thrombi dissolve completely without therapy. Approximately 20% propagate proximally. Propagation usually occurs before embolization. The process of adherence and organization of the venous thrombus does not begin until 5-10 days after thrombus formation. Until this process has been established fully, the nonadherent, disorganized thrombus may propagate and/or embolize.
Not all venous thrombi pose equal embolic risk. Studies have shown that isolated calf vein thrombi carry a limited risk of pulmonary embolism. Furthermore, studies have suggested that isolated calf vein thrombi are smaller and do not cause significant morbidity or mortality if they embolize. Contradictory evidence from several other studies has indicated that isolated calf vein thrombi do embolize and suggests that propagation proximally may occur rapidly and that fatal pulmonary embolism arising from isolated calf vein DVT is a significant risk.
The current diagnostic and therapeutic management of DVT is influenced strongly by the different risks assigned to proximal and calf vein thrombi. The propagation and organization of the venous thrombus usually result in destruction of venous valves and produce varying degrees of venous outflow obstruction. Spontaneous lysis and complete recanalization of established proximal DVT occurs in fewer than 10% of patients, even with anticoagulation. These factors are the most important pathogenic mechanisms in the development of chronic venous insufficiency.
In the US: The exact incidence of DVT is unknown because most studies are limited by the inherent inaccuracy of clinical diagnosis. More importantly, most DVT is occult and usually resolves spontaneously without complication. Existing data that underestimate the true incidence of DVT suggest that about 80 cases per 100,000 persons occur annually. Approximately 1 person in 20 develops DVT over her or his lifetime, and 600,000 hospitalizations for DVT occur annually in the US. In hospitalized patients, the incidence of venous thrombosis is considerably higher and varies from 20-70%. Venous ulceration and venous insufficiency of the lower leg, which are long-term
CLINICAL Section 3 of 10 Author Information Introduction Clinical Differentials Workup Treatment Medication Follow-up Miscellaneous Bibliography History: The signs and symptoms of DVT are related to the degree of obstruction to venous outflow and inflammation of the vessel wall. affect 0. Many thrombi do not produce significant obstruction to .5% of the entire population. Sex: Male-to-female ratio is 1. The bedside diagnosis of venous thrombosis is insensitive and inaccurate.2:1.000 deaths annually in the US. Age: DVT usually affects individuals older than 40 years. Extrapolation of this data reveals that as many as 5 million people suffer from venous stasis and varying degrees of venous insufficiency. which causes 200.complications of DVT. Mortality/Morbidity: Death from DVT is attributed to massive pulmonary embolism. Pulmonary embolism is the leading cause of preventable in-hospital mortality.
venous flow. but this is entirely nonspecific. venous collaterals may develop rapidly. Pain can occur on dorsiflexion of the foot (Homans sign). or extent of the thrombus. and venous wall inflammation may be minimal. Leg pain occurs in 50%. many nonthrombotic conditions produce signs and symptoms suggestive of DVT. usually is confined to the calf muscles or over the course of the deep veins in the thigh. but it also is found in 50% of patients without objectively confirmed DVT. principally unilateral. if present. Studies repeatedly have documented this inherent difficulty of the clinical diagnosis of lower extremity DVT. . location. The pain and tenderness associated with DVT usually does not correlate with the size. the history may include the following: Edema. Warmth or erythema of skin can be present over the area of thrombosis. Clinical signs and symptoms of pulmonary embolism as the primary manifestation occur in 10% of patients with confirmed DVT. Many patients are asymptomatic. however. principally unilateral Tenderness. The following is a list outlining the most sensitive and specific physical findings in DVT: Edema. Massive edema with cyanosis and ischemia (phlegmasia cerulea dolens) is rare. is the most specific symptom. Tenderness occurs in 75% of patients. Conversely. Physical: No single physical finding or combination of symptoms and signs is sufficiently accurate to establish the diagnosis of DVT.
It also is found in more than 50% of patients without DVT. Phlegmasia cerulea dolens Patients with venous thrombosis may develop variable discoloration of the lower extremity. usually low grade.Pain and/or tenderness away from these areas is not consistent with venous thrombosis and usually indicates another diagnosis. indurated. Patients with superficial thrombophlebitis without coexisting varicose veins and with no other obvious etiology (eg. It is therefore very nonspecific. Fever: Fever. High fever is usually indicative of an infectious process such as cellulitis or lymphangitis. soft tissue injury) are at high risk because associated DVT is found in as many as 40% of these patients. . IV drug abuse. may be present. Venous distension and prominence of the subcutaneous veins Superficial thrombophlebitis is characterized by the finding of a palpable. Patients with superficial thrombophlebitis extending to the saphenofemoral junction are also at higher risk for associated DVT. tender subcutaneous venous segment. cordlike. However. this sign is present in less than one third of patients with confirmed DVT. The most common abnormal hue is reddish purple from venous engorgement and obstruction. Homans sign Discomfort in the calf muscles on forced dorsiflexion of the foot with the knee straight has been a time-honored sign of DVT. IV catheters.
DVT is found in 45-70%. The physical findings may suggest acute arterial occlusion. the DVT is clinically silent. but the presence of swelling. painful. In patients with no identified risk . petechiae. The affected extremity is often pale with poor or even absent distal pulses. and cyanotic. In the vast majority of these patients. Causes: The clinical evaluation of patients with suspected DVT is facilitated by an assessment of risk factors. In patients with angiographically proven pulmonary embolism. the leg is cyanotic from massive ileofemoral venous obstruction. Petechiae are often present. The diagnosis of DVT is confirmed in only 20-30% of ED patients with clinically suspected DVT.In rare cases. The leg is usually markedly edematous. Phlegmasia alba dolens Painful white inflammation originally was used to describe massive ileofemoral venous thrombosis and associated arterial spasm. This ischemic form of venous occlusion originally was described as phlegmasia cerulea dolens or painful blue inflammation. The prevalence of DVT in the ED patient population correlates with the number of risk factors present. and distended superficial veins point to this condition. Clinical findings of pulmonary embolism These findings are the primary manifestation of about 10% of patients with DVT.
the number rises to 50%. The following risk factors for DVT have been identified in many different epidemiologic studies: General Age Immobilization longer than 3 days Pregnancy and the postpartum period Major surgery in previous 4 weeks Long plane or car trips (>4 h) in previous 4 weeks Medical Cancer Previous DVT Cerebrovascular accident Acute myocardial infarction (AMI) Congestive heart failure (CHF) . DVT is confirmed in only 11%. In patients with 3 risk factors.factors.
Sepsis Nephrotic syndrome Ulcerative colitis Trauma Multiple trauma CNS/spinal cord injury Burns Lower extremity fractures Vasculitis Systemic lupus erythematosus (SLE) and the lupus anticoagulant Behçet syndrome Homocystinuria Hematologic Polycythemia rubra vera Thrombocytosis .
. For example.Inherited disorders of coagulation/fibrinolysis Antithrombin III deficiency Protein C deficiency Protein S deficiency Factor V Leyden Dysfibrinogenemias and disorders of plasminogen activation Drugs/medications IV drug abuse Oral contraceptives Estrogens Heparin-induced thrombocytopenia The clinical assessment of patients with suspected DVT is often difficult because of the interplay between risk factors and the nonspecific nature of the physical findings. patients deemed to be at high risk for DVT may have a negative duplex ultrasound study. Clinicians have observed that often a discordance is present between the clinical assessment and the results of objective testing.
the probability of DVT is still greater than 20% when the known sensitivity. and negative likelihood ratio of duplex ultrasound are considered. The Wells clinical prediction guide incorporates risk factors. or within 6 months or palliative) 1 Paralysis or recent plaster immobilization 1 Recently bedridden for >3 days or major surgery <4 weeks 1 Localized tenderness along the distribution of the deep venous system 1 Entire leg swelling 1 Calf swelling >3 cm compared to the asymptomatic leg 1 Pitting edema (greater in the symptomatic leg) 1 Collateral superficial veins (nonvaricose) 1 . Wells Clinical Prediction Guide for DVT Clinical Parameter Score Active cancer (treatment ongoing. and the presence or absence of alternative diagnoses. specificity. Combining this with the results of objective testing greatly simplifies the clinical workup of patients with suspected DVT. It was recognized that having an objective method to determine pretest probability would simplify clinical management. The model enables physicians to reliably stratify their patients into high. A clinical prediction guide that quantifies the pretest probability was developed. moderate.In this case. or low risk categories. clinical signs.
279 . JAMA. Septic Thrombophlebitis. 1998.Alternative diagnosis (as likely or > that of DVT) -2 Total of Above Score High probability: Score ³3 Moderate probability: Score = 1 or 2 Low probability: Score £0 Adapted from Anand SS.1094 DIFFERENTIALS Section 4 of 10 Author Information Introduction Clinical Differentials Workup Treatment Medication Follow-up Miscellaneous Bibliography Cellulitis Pulmonary Embolism Thrombophlebitis. et al. Superficial Other Problems to be Considered: .
lymphangitis Extrinsic compression of iliac vein secondary to tumor. renal failure.In approximately 70% of patients with clinically suspected DVT. or nephrotic syndrome Cellulitis. alternate diagnoses ultimately are found as follows: Achilles tendonitis Arterial insufficiency Arthritis Asymmetric peripheral edema secondary to CHF. or abscess Hematoma Lymphedema Muscle or soft tissue injury Neurogenic pain Postphlebitic syndrome Prolonged immobilization or limb paralysis Ruptured Baker cyst Stress fractures or other bony lesions Superficial thrombophlebitis Varicose veins Quick Find Author Information Introduction . hematoma. liver disease.
Click here to take this CME. Superficial Continuing Education CME available for this topic. . Related Articles Cellulitis Pulmonary Embolism Thrombophlebitis. Septic Thrombophlebitis.Clinical Differentials Workup Treatment Medication Follow-up Miscellaneous Bibliography Click for related images.
Some authors have recommended incorporating D-dimer results . but it is relatively nonspecific.Patient Education Click here for patient education. In some centers. A number of studies have evaluated the use of D-dimer. in the diagnosis of DVT. It has been shown to be 93% sensitive for proximal vein thrombosis. WORKUP Section 5 of 10 Author Information Introduction Clinical Differentials Workup Treatment Medication Follow-up Miscellaneous Bibliography Lab Studies: Hematologic and coagulation studies are not required prior to confirming the diagnosis. it has been used as a screening test for DVT. a fibrin degradation product.
factor V Leyden. This explains their lack of specificity. The older quantitative enzyme-linked immunoassay (ELISA) is very accurate but time consuming and not practical for use in the ED. A new rapid qualitative ELISA assay is now available. Different D-dimer assays are available with considerable variation in sensitivity and specificity. D-dimer assays are not "clot specific" and are positive in many other conditions associated with DVT such as recent surgery. and antiphospholipid antibodies can be measured. MI. Some physicians may choose to forego objective ultrasound testing in this scenario. pregnancy. prothrombin 20210A mutation. In patients with low pretest probability for DVT. A rapid bedside qualitative RBC agglutination assay (SimpliRED) is available and is reasonably sensitive for proximal DVT but less so for calf vein DVT. Deficiencies of these factors produce a hypercoagulable state. protein C. antithrombin III. and metastatic cancer. trauma. All D-dimer assays are dependent on the size of the clot. The older qualitative latex agglutination assay is not accurate and should not be used for treating patients with suspected DVT. Protein S. Laboratory investigations for these abnormalities primarily are indicated when DVT is diagnosed in patients younger than 35 years or . a negative D-dimer as measured by the whole blood RBC agglutination assay reduces the probability of DVT to less than 1%.into a management strategy. These are rare causes of DVT.
Duplex ultrasonography and impedance plethysmography (IPG) are the noninvasive tests that have been investigated the most. and lack of availability.when venous thrombosis is detected in unusual sites. presumably . Contrast venography The criterion standard for evaluating patients with suspected DVT has been contrast venography. Imaging Studies: Due to the inherent inaccuracy of clinical diagnosis. Duplex ultrasound Technological advances in ultrasound have permitted the combination of real-time ultrasonic imaging with Doppler flow studies (duplex ultrasound). As a result. contrast-induced DVT. and assessment of risk factors should be used to determine who requires further objective diagnostic testing. technical difficulties. physical examination. Diagnosing DVT and committing patients to the risks of anticoagulation without confirmatory objective testing are unacceptable. noninvasive studies essentially have replaced venography as the initial diagnostic test of choice. For many reasons. the history. interobserver reliability. inadequate studies. The major ultrasound criterion for detecting venous thrombosis is failure to compress the vascular lumen. venography is either contraindicated or nondiagnostic in as many as 20-25% of patients. including allergic reactions.
Many studies have confirmed the diagnostic sensitivity and specificity of duplex ultrasound for proximal vein thrombosis. Standardized ." This procedure is based on recording changes in blood volume of an extremity. The absence of the normal phasic Doppler signals arising from the changes to venous flow provides indirect evidence of venous occlusion. Ultrasound equipment is expensive. venous outflow from the lower extremity is slowed. Duplex ultrasound is also helpful to differentiate venous thrombosis from hematoma. duplex ultrasound may not be able to differentiate between old and new clots. Venous thrombi proximal to the inguinal ligament are also difficult to visualize. IPG has been the initial noninvasive diagnostic test of choice.because of the presence of occluding thrombus. including electrical impedance. In patients with suspected acute recurrent DVT. Sensitivity and specificity for Duplex ultrasound are 98%. and other causes of leg pain and edema. and the blood volume or venous capacitance is increased. The primary disadvantage of duplex ultrasound is its inherent inaccuracy in the diagnosis of calf vein thrombosis. abscess. Nonoccluding thrombi may be hard to detect. and accuracy may vary depending on local expertise. Impedance plethysmography In some countries. Plethysmography is derived from the Greek word meaning "to increase. which are related directly to venous outflow. In the setting of proximal vein thrombosis. Baker cyst. Several different techniques can be used to measure these changes.
In limited studies. .graphs are used to discriminate normal IPG studies from abnormal results. and ileofemoral vein thrombosis above the inguinal ligament. IPG has been shown to be sensitive and specific for proximal vein thrombosis. MRI MRI increasingly has been investigated for evaluation of suspected DVT. MRI is the diagnostic test of choice for suspected iliac vein or inferior vena caval thrombosis. It is insensitive for calf vein thrombosis. In the second and third trimester of pregnancy. Expense. and technical issues limit its use. lack of general availability. MRI is more accurate than duplex ultrasound because the gravid uterus alters Doppler venous flow characteristics. IPG cannot distinguish between thrombotic occlusion and extravascular compression of the vein. In suspected calf vein thrombosis. In many studies. Falsepositive results occur in the setting of significant CHF and raised central venous pressure as well as with severe arterial insufficiency. MRI is more sensitive than any other noninvasive study. the accuracy approaches that of the criterion standard. nonoccluding proximal vein thrombus. contrast venography.
Controversy still exists over the use of noninvasive studies such as duplex ultrasound for the diagnosis of suspected DVT. A number of authors incorrectly recommend the routine use of contrast venography rather than a noninvasive study for suspected DVT on the basis of low sensitivity that has been reported on studies of hospitalized patients post–hip surgery.Nuclear medicine imaging studies: Nuclear medicine studies with I125labeled fibrinogen no longer are recommended for ED patients. the sensitivity of . Reports on the use of noninvasive studies for DVT in asymptomatic hospitalized patients should not be used to determine the optimal evaluation of ED patients with suspected DVT who are usually ambulatory and symptomatic. I125-labeled fibrinogen is no longer available in the US. takes longer than 24 hours to obtain results. Summary . It is relatively insensitive for proximal vein thrombosis. Recognizing that duplex ultrasound is relatively insensitive for calf vein thrombosis only matters if the clinician is inclined to anticoagulate patients with calf vein DVT. If the clinical algorithm for calf vein thrombosis recommends clinical surveillance and serial studies to detect proximal extension. In ambulatory outpatients with suspected DVT.Which test is best? When directly compared. and a significant number of falsepositive studies are obtained. the lack of sensitivity of the noninvasive study is irrelevant. duplex ultrasound has superior sensitivity and specificity over IPG.
Others use the results of a D-dimer assay to guide management. If the duplex study is negative and the patient is low risk. If the patient is high risk but the ultrasound study was negative. treat for DVT. DVT has been ruled out. moderate. A negative D-dimer in . the patient still has a significant probability of DVT. The results from duplex ultrasound are incorporated as follows: If the patient is high or moderate risk and the duplex ultrasound study is positive. and it remains the initial diagnostic test of choice. further evaluation is required. Some authors recommend surveillance with repeat clinical evaluation and ultrasound in 1 week. When discordance exists between the pretest probability and the duplex study result.duplex ultrasound for proximal vein thrombosis is 98%. patients are stratified into 3 risk groups— high. Simplified Clinical Management Strategy for Patients with Suspected DVT Using the pretest probability score calculated from the Wells Clinical Prediction rule. or low. Some authors recommend a venogram to rule out a calf vein DVT that the ultrasound study did not detect.
repeat clinical evaluation and ultrasound in 1 week is recommended. It is important to realize that the clinical prediction rule was developed in a specific subgroup of patients. and prevent . the evaluation and subsequent treatment of this last subgroup of patients must be individualized.combination with a negative ultrasound study significantly lowers the probability of DVT. If the patient is low risk but the ultrasound study is positive. some authors recommend a second confirmatory study such as a venogram before treating for DVT and committing the patient to the risks of anticoagulation. If the patient is moderate risk and the ultrasound study is negative. Therefore. reduce morbidity. and patients already on anticoagulants. Excluded from the model were patients with recurrent DVT. TREATMENT Section 6 of 10 Author Information Introduction Clinical Differentials Workup Treatment Medication Follow-up Miscellaneous Bibliography Emergency Department Care: The primary objectives of the treatment of DVT are to prevent pulmonary embolism. patients with suspected coexistent pulmonary embolism.
Heparin therapy is a necessary adjunct. or pulmonary . intracaval devices introduced intravenously at a remote site and floated into position using fluoroscopy is the procedure of choice. Indications for a filter are severe hemorrhagic complications on anticoagulant therapy. other absolute contraindications to anticoagulation.or minimize the risk of developing the postphlebitic syndrome. unsafe. The Kim-Ray-Greenfield filter is preferred because the long-term patency rates are much higher. Thrombectomy alone is not indicated. or contraindicated. The rationale for thrombectomy is to restore venous patency and valvular function. Thrombectomy is best reserved for patients with massive ileofemoral vein thrombosis (phlegmasia cerulea dolens) when limb viability is at risk. Anticoagulation Thrombolytic therapy for DVT Surgery for DVT Surgical therapy for DVT may be indicated when anticoagulant therapy is ineffective. because rethrombosis occurs very frequently. new or recurrent venous thrombosis. Today. Filters for DVT The concept of inferior vena cava filters arose from the recognition of the late complications of surgical ligation of the inferior vena cava as first proposed by Homans in 1934. The major surgical procedures for DVT are clot removal and partial interruption of the inferior vena cava to prevent pulmonary embolism.
increased ambulation usually is recommended to avoid further venous stasis and propagation of the thrombus. Consultations: Hematology Vascular surgery Radiology Nuclear medicine MEDICATION Section 7 of 10 Author Information Introduction Clinical Differentials Workup Treatment Medication Follow-up Miscellaneous Bibliography Goals of pharmacotherapy in treating venous thrombosis are to reduce morbidity. In North America. and to attain these goals with a minimum number of adverse effects and cost. prevent the development of pulmonary embolism. Drug Category: Anticoagulants -.embolism despite adequate anticoagulation.Anticoagulation remains the mainstay . Compression stockings (routinely recommended) Ambulation: Controversy exists regarding the role of ambulation in the therapy of DVT. bed rest and decreased ambulation usually are recommended theoretically to prevent embolization. prevent the postphlebitic syndrome. In Europe.
the body's primary anticoagulant. inactivates thrombin and inhibits the activity of activated factor X in the coagulation process. Heparin does not affect the size of existing thrombus and has no intrinsic thrombolytic activity. Heparin's anticoagulant effect is related directly to its activation of antithrombin III. The primary reason for this is that heparin has no effect on preexisting nonadherent thrombus. Heparin prevents extension of the thrombus and has been shown to significantly reduce but not eliminate the incidence of fatal and nonfatal pulmonary emboli. Antithrombin III. as well as recurrent thrombosis. Heparin therapy has little effect on the risk of developing postphlebitic syndrome. The larger fragments primarily interact with antithrombin III to inhibit .of initial treatment for DVT. The original thrombus causes venous valvular incompetence and altered venous return leading to a high incidence of chronic venous insufficiency and postphlebitic syndrome. Heparin therapy is associated with complete lysis in fewer than 10% of patients studied with venography after treatment. Heparin is a heterogeneous mixture of polysaccharide fragments with varying molecular weights but with similar biological activity. Regular unfractionated heparin was the standard of care until the recent introduction of low molecular weight heparin (LMWH).
a constant maintenance infusion of 18 U/kg is initiated. This effect is related to the differential half-lives of protein C. and the vitamin K-dependent clotting factors II. The hemorrhagic complications attributed to heparin are thought to arise from the larger higher molecular weight fragments.thrombin. protein S. When IV unfractionated heparin is initiated for DVT. The low molecular weight fragments exert their anticoagulant effect by inhibiting the activity of activated factor X. IX. The aPTT is checked 6 hours after the bolus and adjusted accordingly. Thereafter. Warfarin therapy is overlapped with heparin for 4-5 days until the INR is therapeutically elevated to between 2-3. Heparin pharmacokinetics are complex. and X. with a half-life of 60-90 minutes. It is necessary to overlap heparin with oral warfarin because of the initial transient hypercoagulable state induced by warfarin. VII. the aPTT . The optimal regimen for the treatment of DVT is anticoagulation with heparin or an LMWH followed by full anticoagulation with oral warfarin for 3-6 months. Some evidence exists that even longer anticoagulation with warfarin is appropriate in certain cases.5 times control. The aPTT is repeated every 6 hours until 2 successive aPTTs are therapeutic. Long-term anticoagulation definitely is indicated for patients with recurrent venous thrombosis and/or persistent or irreversible risk factors. After an initial bolus of 80 U/kg. the goal is to achieve and maintain an elevated aPTT of at least 1.
Heparin-induced thrombocytopenia is not infrequent. platelet aggregation induced by heparin may trigger venous or arterial thrombosis with significant morbidity and mortality. and Ardeparin. and its half-life permits single or twice daily dosing. Its use in the outpatient treatment of DVT and pulmonary embolism has been evaluated in a number of studies. Dalteparin. Its activity is measured in units of factor X inactivation. the use of LMWH. The increased bioavailability and prolonged half-life of LMWH allow . LMWH is administered SC. have received FDA approval for the treatment of DVT. or initiation of therapy with warfarin alone. All patients who develop thrombocytopenia while on heparin are at risk. LMWH is prepared by selectively treating unfractionated heparin to isolate the low (<9. the subset of patients who develop thrombosis is unpredictable. Alternatives include the substitution of porcine for bovine heparin. Unfortunately. 3 LMWH preparations. The dose is weight adjusted.000 Da) molecular weight fragments. Tinzaparin has been approved for in-hospital treatment of DVT. Enoxaparin. In this condition. At the present time.is monitored every 24 hours as well as the hematocrit and platelet count. and monitoring of the aPTT is not required.
Outpatient management is not recommended if the patient has proven or suspected concomitant pulmonary embolism. NSAIDs. Outpatient treatment of acute DVT using LMWH has been evaluated successfully in a number of studies and is currently the treatment option of choice if the patient meets the necessary criteria. Does not actively lyse but is able to inhibit further thrombogenesis. severe liver disease. Adult Dose 80 U/kg IV bolus. dipyridamole. active bleeding. tetracycline.Drug Name Heparin (Hep-Lock) -. history of heparin-induced thrombocytopenia Interactions Digoxin. which is used as preservative. and antihistamines may decrease effects. morbid obesity. hemophilia. dextran. aspirin. preservative-free heparin is recommended to avoid possible toxicity (gasping syndrome) by benzyl alcohol. or poor follow-up. caution in severe hypotension and shock .for outpatient treatment of DVT using once or twice daily SC treatment regimens. and hydroxychloroquine may increase heparin toxicity Pregnancy A . subacute bacterial endocarditis.Safe in pregnancy Precautions In neonates. extensive ileofemoral DVT. significant comorbidities. Prevents reaccumulation of a clot after a spontaneous fibrinolysis.Augments activity of antithrombin III and prevents conversion of fibrinogen to fibrin. nicotine. followed by 18-U/kg/h maintenance infusion Monitor aPTT and titrate maintenance dose to effect Pediatric Dose Administer as in adults Contraindications Documented hypersensitivity. renal failure.
Unsafe in pregnancy Precautions Do not switch brands after achieving therapeutic . cholestyramine. salicylates. adjust according to desired INR Infants may require doses at or near high end of this range Contraindications Documented hypersensitivity. clofibrate. colestipol. risk of CNS hemorrhage. nalidixic acid.Interferes with hepatic synthesis of vitamin K-dependent coagulation factors. pulmonary embolism. estrogens. sulfonylureas. or respiratory tract Interactions Drugs that may decrease anticoagulant effects include griseofulvin. rifampin. ethacrynic acid. propoxyphene. and sulindac Pregnancy D . phenylbutazone. metronidazole. phenylbutazone.34 mg/kg/d. and sucralfate Medications that may increase anticoagulant effects of warfarin include oral antibiotics. sulfonamides. phenytoin. diazoxide. gemfibrozil. miconazole. Adult Dose 2-10 mg/d PO Pediatric Dose Weight-based dose of 0. oral contraceptives. glutethimide. sulfonamides.05-0. severe liver or kidney disease. ketoconazole. GU. phenytoin. acetaminophen. carbamazepine. allopurinol. chloral hydrate. vitamin K. barbiturates. open wounds or bleeding of GI. spironolactone. Used for prophylaxis and treatment of venous thrombosis. cerebral aneurysms.Drug Name Warfarin (Coumadin) -. anabolic steroids. and thromboembolic disorders. nafcillin. chloramphenicol. disulfiram. Dose must be individualized and adjusted to maintain INR between 2-3. cimetidine.
Slightly affects thrombin and clotting time and preferentially increases inhibition of factor Xa. administer 1. sulfinpyrazone. heparin-associated thrombocytopenia may occur with fractionated LMWH. salicylates. patients with protein C or S deficiency are at risk of developing skin necrosis Drug Name Enoxaparin (Lovenox) -. discontinue drug and initiate alternate therapy.LMWH used in treatment of DVT and pulmonary embolism as well as DVT prophylaxis. alternatively.5 mg/kg SC qd Pediatric Dose Not established The following doses have been suggested: <2 months: 0. major bleeding. Enhances inhibition of factor Xa and thrombin by increasing antithrombin III activity. NSAIDs. Adult Dose 1 mg/kg SC bid. elevation of hepatic transaminases may occur but is reversible. aspirin.Usually safe but benefits must outweigh the risks. Precautions If thromboembolic event occurs despite LMWH prophylaxis. 1 mg of protamine sulfate reverses effect of approximately 1 mg of enoxaparin if significant bleeding complications develop .75 mg/kg/dose bid 2 months to 18 years: 0. Average duration of treatment is 7-14 d.response. caution in active tuberculosis or diabetes. and ticlopidine may increase risk of bleeding Pregnancy B .5 mg/kg/dose bid Contraindications Documented hypersensitivity. history of heparin-induced thrombocytopenia Interactions Platelet inhibitors or oral anticoagulants such as dipyridamole.
Enhances inhibition of factor Xa and thrombin by increasing antithrombin III activity. major bleeding. and ticlopidine may increase risk of bleeding Pregnancy B . NSAIDs. Adult Dose 175 U/kg SC qd. adult dose suggested Contraindications Documented hypersensitivity. prevention of pulmonary embolism. heparin-associated thrombocytopenia may occur with fractionated low-molecular-weight heparins. aspirin. heparin-induced thrombocytopenia (current or history of) Interactions Platelet inhibitors or oral anticoagulants such as dipyridamole. In addition. Average duration of treatment is 7-14 d.Drug Name Tinzaparin (Innohep) -. Precautions If thromboembolic event occurs despite LMWH prophylaxis. restoration .Used in hospitalized patients. at same time each day for >6 d and until patient is adequately anticoagulated with warfarin (INR >2 for 2 consecutive d) Pediatric Dose Not established. 1 mg of protamine sulfate will reverse effect of approximately 100 U of tinzaparin if significant bleeding complications develop Drug Category: Thrombolytics -. discontinue drug and initiate alternate therapy. elevation of hepatic transaminases may occur but is reversible. salicylates. preferentially increases inhibition of factor Xa. sulfinpyrazone. Advantages include prompt resolution of symptoms.Usually safe but benefits must outweigh the risks.Offer significant advantages over conventional anticoagulant therapy.
The uncertainty regarding . Thrombolytic therapy is also not effective once the thrombus is adherent and begins to organize. preservation of venous valvular function. Preliminary evidence suggests the incidence of postphlebitic syndrome at 3 years is reduced by half but certainly not entirely eliminated. The thrombolytic agent that acts on the surface of the clot may not be able to penetrate and lyse the thrombus. Unfortunately.of normal venous circulation. rethrombosis. The unproven assumption is that the degree of lysis seen on the posttreatment venogram is predictive of future venous valvular insufficiency and late (5-10 y) development of postphlebitic syndrome. Venous thrombi in the legs are often large and associated with complete venous occlusion. including the small but potentially fatal risk of intracerebral hemorrhage. the data from many published studies indicate that thrombolytic therapy is more effective than heparin in achieving vein patency. Thrombolytic therapy does not prevent clot propagation. the majority of patients with DVT have absolute contraindications to thrombolytic therapy. The hemorrhagic complications of thrombolytic therapy are formidable (about 3 times higher). or subsequent embolization. Heparin therapy and oral anticoagulant therapy always must follow a course of thrombolysis. and prevention of postphlebitic syndrome. Nevertheless.
thrombolytic therapy is not recommended routinely for DVT at most centers but should be considered in patients with massive ileofemoral vein thrombosis or in young patients with acute onset of extensive DVT. history of cerebrovascular accident. More expensive than streptokinase. Acts on endogenous fibrinolytic system and converts plasminogen to enzyme plasmin. intracranial neoplasm Interactions Thrombolytic enzymes.Drug Name Urokinase (Abbokinase) -. may increase risk of bleeding .thrombolytic therapy likely will continue. Plasmin degrades fibrin clots. Advantage is that it is nonantigenic. internal bleeding. When used for purely local fibrinolysis. and other plasma proteins. alone or in combination with anticoagulants and antiplatelets. given as local infusion directly into area of thrombus and with no bolus.Direct plasminogen activator isolated from human fetal kidney cells grown in culture. smaller bolus of 250. recent trauma including cardiopulmonary resuscitation. Dose should be adjusted to achieve clot lysis or patency of affected vessel.000 U IV may be given followed by infusion at 500-2000 U/kg/h Pediatric Dose Administer as in adults Contraindications Documented hypersensitivity. Adult Dose 4400 U/kg IV bolus followed by maintenance infusion at 4400 U/kg/h for 1-3 d For regional thrombus-directed therapy. intracranial or intraspinal surgery or trauma. which limits its use. Currently. fibrinogen.
000 U/h for 1-3 d Pediatric Dose Administer as in adults Contraindications Documented hypersensitivity.complications Pregnancy B . Streptase) -. An increase in fibrinolytic activity that degrades fibrinogen levels for 24-36 h takes place with intravenous infusion of streptokinase. warfarin.Acts with plasminogen to convert plasminogen to plasmin. Precautions Caution in patients receiving intramuscular administration of medications and those with severe hypertension or trauma or surgery in previous 10 d. TT. severe uncontrolled arterial hypertension Interactions Antifibrinolytic agents may decrease effects of streptokinase. Plasmin degrades fibrin clots as well as fibrinogen and other plasma proteins. aPTT. Adult Dose 250. monitor therapy by performing PT. and aspirin may increase risk of bleeding Pregnancy C .Safety for use during pregnancy has not been established. or fibrinogen approximately 4 h after initiation of therapy Drug Name Streptokinase (Kabikinase.Usually safe but benefits must outweigh the risks. avoid dislodging a possible deep vein thrombi. diathesis. do not measure blood pressure in lower extremities. active internal bleeding. aneurysm. Precautions Caution in severe hypertension. intracranial neoplasm. intramuscular . heparin.000 U IV bolus followed by an infusion at 100.
AMI.Thrombolytic agent for DVT or pulmonary embolism. Safety and efficacy of this regimen with coadministration of heparin and aspirin during the first 24 h after symptom onset have not been investigated. aPTT. severe uncontrolled hypertension. measure hematocrit. do not take blood pressure in the lower extremities as it may dislodge a possible deep vein thrombi. <2 mo history of cerebrovascular accident. or fibrinogen should be monitored 4 h after initiation of therapy Drug Name Alteplase. suspicion of . platelet count. and trauma or surgery in the previous 10 d. bleeding diathesis. also avoid with intracranial hemorrhage when performing pretreatment evaluation.administration of medications. and pulmonary embolism. active internal bleeding. intracranial or intraspinal surgery or trauma. PT. PT. arteriovenous malformation or aneurysm. or fibrinogen levels before therapy is implemented. A tissue plasminogen activator (tPA) produced by recombinant DNA and used in the management of acute ischemic stroke. aPTT. TT. either TT or aPTT should be less than twice the normal control value following infusion of streptokinase and before (re)instituting heparin. t-PA (Activase) -. Adult Dose Front-loaded regimen recommended 15 mg IV bolus initially followed by 50 mg IV over the next 30 min and then 35 mg IV over the next 1 h Pediatric Dose Not established Contraindications Documented hypersensitivity. recent intracranial surgery. intracranial neoplasm. TT.
abciximab) may increase risk of bleeding before. intracranial neoplasm. dipyridamole. arteriovenous malformation or aneurysm. or serious head trauma or recent previous stroke. or after alteplase therapy. seizure at onset of stroke. during. either heparin or alteplase may cause bleeding complications Pregnancy C . doses >0. may give heparin with and after alteplase infusions to reduce risk of rethrombosis.9 mg/kg to manage acute ischemic stroke. especially at arterial puncture sites.9 mg/kg may cause ICH FOLLOW-UP Section 8 of 10 Author Information Introduction Clinical Differentials Workup Treatment Medication Follow-up Miscellaneous Bibliography Further Inpatient Care: . do not use >0. control and monitor blood pressure frequently during and following alteplase administration (when managing acute ischemic stroke).subarachnoid hemorrhage. uncontrolled hypertension. or bleeding diathesis Interactions Drugs that alter platelet function (aspirin. Precautions Monitor for bleeding.Safety for use during pregnancy has not been established. active internal bleeding. do not administer with a history of intracranial hemorrhage. with coadministration of vitamin K antagonists.
selected patients qualify for outpatient treatment only if adequate home care . With the introduction of low molecular weight heparin.Most patients with confirmed proximal vein DVT may be treated safely on an outpatient basis. Low molecular weight heparin and warfarin are overlapped for about 5 days until the international normalized ratio (INR) is therapeutic. If inpatient treatment is necessary. low molecular weight heparin is effective and obviates the need for IV infusions or serial monitoring of the PTT. Exclusion criteria for outpatient management are as follows: Suspected or proven concomitant pulmonary embolism Significant cardiovascular or pulmonary comorbidity Morbid obesity Renal failure Unavailable or unable to arrange close follow-up care Patients are treated with a low molecular weight heparin and instructed to initiate therapy with warfarin 5 mg PO the next day.
hematemesis. monitor monthly. then weekly for several weeks. Subsequent episodes should be treated for at least 1 year. cancer. the prothrombin time (PT) must be monitored daily until target achieved.and close medical follow-up care can be arranged. Significant bleeding (ie. gastrointestinal hemorrhage) should be investigated thoroughly since anticoagulant therapy may unmask a preexisting disease (eg. . When the patient is stable. For the first episode.000. Many physicians do not treat calf vein DVT with anticoagulation unless proximal extension is documented objectively with close clinical surveillance. taking into account local preferences. Inability to monitor INR precludes outpatient treatment of DVT. peptic ulcer disease. patients with isolated calf vein DVT are admitted for full anticoagulant therapy. the availability of follow-up care. Further Outpatient Care: Treatment for isolated calf vein DVT is best individualized. The activated partial thromboplastin time (aPTT) must be monitored every 6 hours while the patient is on IV heparin until the dose stabilizes. arteriovenous malformation). patient reliability. At some centers. patients should be treated for 3-6 months. and an assessment of ongoing risk factors. While on warfarin. Platelets also should be monitored and heparin discontinued if platelets fall below 75. hematuria.
Patients with suspected DVT but negative noninvasive studies need to be reassessed by their primary care provider within 3-7 days. DVT prophylaxis for patients scheduled to undergo major surgery is well recognized. Transfer: Transfers may be necessary for patients with special concerns such as those with inherited coagulation disorders. Deterrence/Prevention: Prophylaxis for DVT is required for all patients who develop risk factors. Patients with ongoing risk factors may need to be restudied at that time to detect proximal extension because of the limited accuracy of noninvasive tests for calf vein DVT. surgical therapy. or insertion of a filter. Recently a large multicenter double-blind placebo-controlled trial showed a 63% reduction in the incidence of DVT/pulmonary embolism in .Patients with suspected or diagnosed isolated calf vein DVT may be discharged safely on a nonsteroidal anti-inflammatory drug (NSAID) or aspirin with close follow-up care and repeat diagnostic studies in 37 days to detect proximal extension. patients with isolated calf vein DVT are admitted for full anticoagulant therapy. Transfers may be required depending on local expertise for treatment with thrombolytics. At certain centers.
For severe hemorrhage. Patients who hemorrhage while receiving heparin are best treated by discontinuing the drug. age. The treatment of hemorrhage while on heparin depends on the severity of the bleeding and the extent to which the aPTT is elevated above the therapeutic range. Hemorrhagic complications are the most common adverse effects of anticoagulant therapy. drug interactions. Severe lifethreatening hemorrhage is managed with fresh frozen plasma in . The risk of hemorrhage on heparin is approximately 5%. Complications: Acute pulmonary embolism still may occur despite adequate anticoagulation. The risk is conditioned by other factors. such as intracranial or massive gastrointestinal bleeding. Protamine should be administered at the same time that the infusion is stopped. including poor follow-up. heparin may be neutralized by protamine at a dose of 1 mg for every 100 units. The risk of bleeding on warfarin is not linearly related to the elevation of the INR. and preexisting disorders that predispose to bleeding.general medical patients admitted to the hospital. Patients who hemorrhage while receiving oral warfarin are treated by withholding the drug and administering vitamin K. Treatment with fresh frozen plasma or platelet infusions is ineffective. and the aPTT usually returns to normal within a few hours. The half-life is relatively short.
calf DVTs occasionally propagate into the proximal system. the mortality is decreased 5.to 10-fold. However.Phlegmasia cerulea dolens (very rare but should be considered a surgical emergency) Prognosis: All patients with proximal vein DVT are at long-term risk of developing chronic venous insufficiency. suspected calf DVTs should be observed every 3-5 days for 10 days and treated aggressively if they propagate into the popliteal or femoral system.addition to vitamin K. About 20% of untreated proximal (above the calf) DVTs progress to pulmonary emboli. pain and edema in the affected limb without new clot formation) Soft-tissue ischemia associated with massive clot and very high venous pressures . Additional complications include the following: Systemic embolism Chronic venous insufficiency Postphlebitic syndrome (ie. Patient Education: . and 10-20% of these are fatal. DVT confined to the calf virtually never causes clinically significant emboli and thus does not require anticoagulation. With aggressive anticoagulant therapy. Therefore.
Discourage prolonged immobility. MISCELLANEOUS Section 9 of 10 Author Information Introduction Clinical Differentials Workup Treatment Medication Follow-up Miscellaneous Bibliography Medical/Legal Pitfalls: Failure to consider the diagnosis in patients with risk factors Failure to recommend repeat noninvasive studies and reassessment in high-risk patients with negative initial evaluations Special Concerns: Superficial thrombophlebitis Superficial thrombophlebitis often is associated with DVT in 2 specific settings. particularly on plane rides and long car trips. The following high-risk groups require further evaluation for DVT: Superficial thrombophlebitis in the absence of coexisting venous .Advise women taking estrogen of the risks and common symptoms of thromboembolic disease.
The incidence is lower than DVT. Axillary/subclavian vein thrombosis This first was described by Paget (1875) and von Schrötter (1884) and is sometimes referred to as Paget-von Schrötter syndrome. The pathophysiology is similar to that of DVT. fewer venous valves. Bed rest is not recommended. higher rates of blood flow.varices and no other obvious etiology Involvement of the greater saphenous vein above the knee. and the etiologies overlap. The increased use of subclavian catheters for chemotherapy and parenteral nutrition has resulted in a dramatic increased incidence of proven . of the lower extremities because of decreased hydrostatic pressure. Some centers recommend full anticoagulation even with negative noninvasive studies for the high-risk groups mentioned above. especially if it extends to the saphenofemoral junction Uncomplicated superficial thrombophlebitis may be treated symptomatically with heat. and less frequent immobility of the upper arm. Thoracic outlet compression from cervical ribs or congenital webs may precipitate axillary/subclavian venous thrombosis. Catheter-induced thrombosis is increasingly a common cause of this condition. An alternative approach involves symptomatic care alone with close follow-up and repeat noninvasive testing in 24-72 hours. and compression hose. NSAIDs. Full anticoagulation then is reserved only for those patients with proven proximal vein DVT.
Thrombolytic therapy is the treatment of choice for axillary/subclavian venous thrombosis.thrombosis. Ultrasonography and venography are the diagnostic tests of choice. Catheterinduced thrombosis may require removal of the device. Similarly. Duplex ultrasound is accurate for the evaluation of the internal jugular vein and its junction with the subclavian vein where the innominate vein begins. Thrombolysis is best accomplished with local administration of the thrombolytic agent directly at the thrombus. and the thrombolytic agent is administered as a direct infusion. In the presence of anatomic abnormalities. surgical therapy is recommended to minimize long-term morbidity and recurrence. Fatal or massive pulmonary embolism is extremely rare. Locally infused thrombolytic agents have been used successfully and are currently the treatment of choice. Restoration of venous patency is more critical for the prevention of chronic venous insufficiency in the upper extremity. Heparin usually is given concurrently to prevent rethrombosis. After completion of a venographic study. . Venographic assessment for clot lysis is repeated every 4-6 hours until venous patency is restored. Ultrasonography may be falsely negative because of collateral blood flow. pulmonary artery catheters are associated with a high incidence of internal jugular and subclavian vein thrombosis. a catheter is floated up to the site of the clot. Pulmonary embolism occurs in approximately 10% of patients.
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