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DEEP VEIN THROMBOSIS BASICS DESCRIPTION Development of single or multiple blood clots within the deep veins of the

extremities or pelvis, usually accompanied by inflammation of the vessel wall. The major clinical consequence is embolization, usually to the lung, that is frequently lifethreatening. System(s) affected: Cardiovascular Genetics: Inherited thrombophilic states increase risk for venous thromboembolic disease Incidence/Prevalence in USA: Common (approximately 250,000 hospitalizations and 50,000 deaths from complications of venous thromboembolic disease) Predominant age: Mean age of 60 (increasing age is an independent risk factor) Predominant sex: Male > Female (1.2 : 1) SIGNS & SYMPTOMS Many cases are completely asymptomatic, diagnosed after embolization Physical exam is only 30% accurate for DVT Limb pain (common) Limb swelling (common) Leg pain on dorsiflexion of the foot (Homan sign; unreliable test for DVT) Palpable tender cord in affected limb (uncommon) Warmth of skin over area of thrombosis (uncommon) Redness of skin over area or thrombosis (uncommon) Fever (uncommon, except in septic thrombophlebitis) Non-tender swelling of collateral superficial veins (uncommon) Massive edema with cyanosis and ischemia; a medical emergency (Phlegmasia cerulea dolens, rare) Pain on percussion of the medial tibia (Lisker sign) Pain on compression of the calf against the tibia in the anteroposterior plane (Bancroft or Moses sign) CAUSES Venous stasis Injury to vessel wall Abnormalities of coagulation RISK FACTORS Clinical risk factors: Increasing age Trauma, especially long bone fractures or crush injuries Surgery (most commonly orthopedic, gastrointestinal, and genitourinary) Prolonged immobility Pregnancy, especially the puerperium Indwelling central venous catheters Travel (> 4 hours) Hormone replacement therapy Tamoxifen therapy Selective estrogen receptor modulator therapy (SERMs; raloxifene [Evista]) High altitude (> 14,000 feet)

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Pathological risk factors: Prior DVT or pulmonary embolism Inherited hypercoagulable states (thrombophilic states) - Factor V Leiden mutation resulting in resistance to activated protein C - Prothrombin mutation (G20210A) - Hyperhomocysteinemia - Protein C deficiency - Protein S deficiency - Antithrombin III defi ciency - Homocysteinuria (rare) Other hypercoagulable states - Antiphospholipid syndrome (lupus anticoagulant, anticardiolipin antibodies) - Elevated factor VIII, IX, XI - Elevated fibrinogen - Elevated vonWillebrand factor Malignancy Obesity Nephrotic syndrome Polycythemia vera Campylobacter jejuni bacteremia (very rare) Myeloproliferative disorders Vitamin deficiencies (B6, B12, folate) Heparin-induced thrombocytopenia Acute myocardial infarction Neurologic disease with paralysis (acute spinal cord injury, CVA) DIAGNOSIS DIFFERENTIAL DIAGNOSIS Cellulitis Ruptured synovial cyst (Baker cyst) Lymphedema Extrinsic compression of vein by tumor or enlarged lymph nodes Pulled, strained, or torn muscle Compartment syndrome Localized allergic reaction Filariasis (in developing countries) LABORATORY D-dimer (sensitive but not specific; has a high negative predictive value) Baseline labs: CBC, platelet count, aPTT, PT/INR Labs for idiopathic (no known inciting event) DVT First tier of testing: Factor V Leiden, G20210A prothrombin, serum homocysteine, factor VIII level, and lupus anticoagulant Second tier of testing: Protein C and S antigen levels, antithrombin activity, and anticardiolipin antibodies Drugs that may alter lab results: Heparin, estrogens may lower antithrombin III levels Coumadin affects protein C and protein S function so may interfere with functional assays of these proteins Disorders that may alter lab results: Thrombosis itself lowers antithrombin III levels so any workup for antithrombin III deficiency must be performed after patient has completed therapy Syphilis and systemic lupus erythematosus are associated with increased antiphospholipid antibodies

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PATHOLOGICAL FINDINGS Clot consisting predominantly of red blood cells, with some platelets and fibrin attached to vessel wall at one end with proximal end floating free in the lumen. Varying degrees of inflammation of the vessel wall are present. DVT may be the sentinel event for an underlying malignancy or thrombophilia SPECIAL TESTS N/A IMAGING Imaging studies are necessary to diagnose or rule out suspected DVT Compression ultrasonography; noninvasive, highly sensitive and specific for popliteal and femoral thrombi. Disadvantages include poor ability to detect calf vein thrombi, does not identify clots in pelvic veins or vena cava, is operator-dependent, does not distinguish acute from chronic thrombi, and is difficult to distinguish extrinsic vein compression from intravenous clot. Contrast venography is the gold standard test (i.e., most sensitive and specific) but should not be the initial screening tool. Disadvantages include discomfort, technical difficulty and small risk of morbidity. Impedance plethysmography (IPG); probably as accurate as duplex ultrasound, less operator dependency, but poor at detecting calf vein thrombi. Not widely available. Magnetic resonance venography: as accurate as contrast venography; may be useful for patients with contraindications to IV contrast material 125 I-fibrinogen scan; detects only active clot formation; very good at detecting ongoing calf thrombi. Major disadvantage is that it takes 4 hours for results. This test has generally been supplanted by contrast ultrasonography and IPG. TREATMENT APPROPRIATE HEALTH CARE Patients with complicated DVT (see Medications Section) should usually be admitted, others can be managed as outpatients GENERAL MEASURES For hospitalized patient - intravenous anticoagulation, a brief period of bedrest, and close observation for embolic events SURGICAL MEASURES When anticoagulants and thrombolytics are contraindicated, filtering devices (umbrellas) can be inserted into the vena cava to trap emboli before reaching the lungs. Very large clots can be surgically removed in certain circumstances. ACTIVITY Bedrest for 1-2 days, then gradual resumption of normal activity, with avoidance of prolonged immobility DIET No special diet, however patients taking warfarin need to be aware that foods high in vitamin K can affect their PT PATIENT EDUCATION Advise women taking estrogen of the risks, and the common symptoms of thromboembolic disease Advise women with an inherited or acquired thrombophilia or a history of thrombosis to avoid oral contraceptives and hormone replacement therapy Women with personal or family history of thrombosis should be offered screening for inherited or acquired thrombophilias (clotting disorders) Discourage prolonged immobility MEDICATIONS DRUG(S) OF CHOICE DVT is complicated if any of these are present: evidence of pulmonary embolism, recent surgery, peptic ulcer disease, malignant hypertension, increased risk of falling, extensive proximal DVT, heparin allergy or history of heparin-induced thrombocytopenia, known bleeding disorder, active bleeding, comorbid illness with high risk of bleeding, renal insufficiency, pregnancy, known protein C or S deficiency, noncompliance, poor follow-up, inadequate home support, inaccessibility to outpatient monitoring, morbid obesity, age < 18 years, age > 75 years, and severe leg pain and swelling.

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Uncomplicated DVT : LMWH (can be administered in an outpatient setting) [enoxaparin (Lovenox) 1 mg/ kg/dose bid SC; dalteparin (Fragmin)]. No laboratory monitoring required. Complicated DVT Heparin 80 units/kg IV bolus followed by continuous infusion starting at 18 units/kg/hr. Adjust dosage to aPTT of 2-3x control OR Enoxaparin (Lovenox) either 1mg/kg/dose bid SC or 1.5mg/kg/qd SC. No laboratory monitoring required. Maintenance therapy: Warfarin (Coumadin) may be started on the first day, once therapeutic anticoagulation is reached, 5mg qDay and adjusting based on prothrombin time (PT) with a target PT of 1.5-2x control. Continue heparin until target PT level is achieved (INR 2-3). For patients with contraindications to warfarin, LMWH or heparin can be continued SC for the duration of treatment. Dalteparin (Fragmin) is approved for DVT prophylaxis Contraindications: Severe active bleeding, neurosurgical procedure within 30 days, pregnancy (warfarin only), previous adverse reaction to the drug (other than bleeding, which is a known side effect) Relative contraindications: Recent hemorrhage, recent surgical procedure other than neurosurgery, history of significant peptic ulcer disease, recent nonembolic stroke Precautions: Observe patient for signs of embolization, further thrombosis or bleeding Avoid IM injections. Periodically check stool and urine for occult blood, monitor complete blood counts including platelets. Heparin - thrombocytopenia and/or paradoxical thrombosis with thrombocytopenia Warfarin - necrotic skin lesions (typically breasts, thighs, buttocks) LMWH - adjust dosage in renal insufficiency Significant possible interactions: Agents that intensify the response to oral anticoagulants: Alcohol, allopurinol, amiodarone, anabolic steroids, androgens, many antimicrobials, cimetidine, chloral hydrate, disulfiram, all NSAIDs, sulfinpyrazone, tamoxifen, thyroid hormone, vitamin E, ranitidine, salicylates, acetaminophen Agents that diminish the response to anticoagulants: Aminoglutethimide, antacids, barbiturates, carbamazepine, cholestyramine, diuretics, griseofulvin, rifampin, oral contraceptives ALTERNATIVE DRUGS Thrombolytic agents (urokinase, streptokinase, alteplase [tissue plasminogen activator]) are effective in dissolving clots and are currently investigational for treatment of DVT. In current clinical practice should be reserved for massive thromboembolic disease. The same contraindications apply as to anticoagulants. If warfarin is contraindicated, heparin can be given in the ambulatory setting by intermittent SC self-injection (see Pregnancy in Miscellaneous Section below) FOLLOWUP PATIENT MONITORING Heparin: aPTT monitored several times a day until dose stabilizes. Discontinue heparin if platelets < 75,000 Warfarin: PT/INR daily until target achieved, then weekly for several weeks, then (if stable) monthly Duration of treatment with warfarin after venous thrombotic event 3 months of warfarin - Event provoked by surgery, trauma or immobilization

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6 months of warfarin - First unprovoked event - Event provoked by pregnancy, peripartum, or OCPs/HRT - Proximal vein thrombosis - Pulmonary embolism provoked by surgery, trauma or immobilization - Age > 45 with DVT - Heterozygous for Factor V Leiden with event - Heterozygous for G20210A prothrombin mutation with event 6-18 months of warfarin. Active cancer, continued immobilization, venous insufficiency, Protein C/S deficiency, or elevated factor VIII Indefinite treatment with warfarin - Recurrent DVT, PE or other thrombotic event - Life threatening event (large PE, limb threatening DVT) - Cerebral or visceral vein thrombosis - Antithrombin deficiency with event - Homozygous for Factor V Leiden with event - Combined clotting disorders (eg, Factor V Leiden plus elevated homocysteine) with event - Antiphospholipid antibodies with event Monitoring with LMWH: No monitoring required, however in select patients (eg, those with severe renal insufficiency, morbid obesity) an antifactor Xa activity level may help guide titration of therapy. This assay is limited by controversy over its correlation to therapeutic efficacy and ability to predict hemorrhage in high risk patients. Investigate significant bleeding (eg, hematuria or GI hemorrhage) since anticoagulant therapy may unmask a pre-existing lesion (e.g., cancer, peptic ulcer disease, or arteriovenous malformation) PREVENTION/AVOIDANCE Avoid prolonged immobility Low-estrogen birth control pills when possible Surgical patients need active prophylaxis: Low dose SC heparin with dosage adjusted to slightly prolong the aPTT, low dose warfarin, LMWH and intermittent mechanical compression of the legs reduce the risks of DVT. Dalteparin (Fragmin) is approved for DVT prophylaxis POSSIBLE COMPLICATIONS Pulmonary embolism (fatal in 10-20%) Arterial embolism (paradoxical embolization) with AV shunting Chronic venous insufficiency Post-phlebitic syndrome (pain and swelling in affected limb without new clot formation) Treatment-induced hemorrhage Soft tissue ischemia associated with massive clot and very high venous pressures phlegmasia cerulean dolens (very rare but is a surgical emergency) EXPECTED COURSE/PROGNOSIS About 20% of untreated proximal (ie, above the calf) DVTs progress to pulmonary emboli and 10-20% of those are fatal. With aggressive anticoagulant therapy the mortality is decreased five to tenfold. DVT confined to the infrapopliteal veins has a small risk of embolization. However these can propagate into the proximal system - follow with serial IPG or duplex ultrasound. Some recommend full anticoagulation therapy for all patients with calf vein DVT because of a 25% one-year risk of developing chronic venous insufficiency. Skin necrosis is a possibility in patients with protein C deficiency who also take warfarin

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MISCELLANEOUS ASSOCIATED CONDITIONS Malignant neoplasm (1/5 of all venous thromboembolic disease) Mild to moderate hyperhomocysteinemia Inherited thrombophilias Antiphospholipid antibody syndrome Budd-Chiari syndrome (hepatic vein thrombosis) Renal vein thrombosis AGE-RELATED FACTORS Pediatric: In this age group, patients with DVT in absence of preceding trauma should be worked up for inherited coagulopathy Geriatric: More common because predisposing conditions are more common Others: N/A PREGNANCY Warfarin (Coumadin) is a teratogen and is therefore contraindicated in pregnancy. Treat pregnant women with DVT with full dose heparin initially followed by subcutaneous heparin starting at 15,000 units twice daily with target aPTT of 1.5-2x control. Warfarin is considered safe with breast-feeding Septic thrombophlebitis, usually associated with childbirth, requires antibiotic therapy as well as anticoagulation SYNONYMS Deep venous thrombophlebitis ICD-9-CM 451.19 Phlebitis and thrombophlebitis of deep vessels of lower extremities, other 415.19 Pulmonary embolism and infarction, other 453.8 Embolism and thrombosis of other specified veins 289.81 Primary hypercoagulable state 289.82 Secondary hypercoagulable state SEE ALSO Pulmonary embolism Factor V Leiden Protein C defi ciency Protein S defi ciency Prothrombin 20210 (Mutation) Antithrombin defi ciency OTHER NOTES N/A ABBREVIATIONS DVT = deep vein thrombosis IPG = impedance plethysmography INR = international normalized ratio LMWH = low molecular weight heparin aPTT = activated partial thromboplastin time AV = arteriovenous REFERENCES Brown DF. Treatment options for deep venous thrombosis. Emerg Med Clin North Am 2001;19(4):913-23 Collet JP, Montalescot G, Fine E, et al. Enoxaparin in unstable angina patients who would have been excluded from randomized pivotal trials. J Am Coll Cardiol 2003;41:814 Heit JA: Risk factors for venous thromboembolism. Clin Chest Med 2003;24(1):1-12

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