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deep vein thrombosis (DVT)

Deep vein thrombosis (DVT) is the clotting of blood in the deep veins of the leg or arm, generally accompanied by inflammation (thrombophlebitis). Also see venous thromboembolism. Etiology: risk factors <odds ratio in parenthesis> 1) immobilization (8.0), hospitalization - long-distance travel (prolonged sitting) [13,28] 2) major surgery (21.7) a) orthopedic surgery - knee or hip surgery - 50% incidence of postoperative DVT without prophylaxis - mean times to DVT post-surgery [18] - knee replacement: 2 weeks - hip fracture: 3 weeks - total hip replacement: 4 weeks b) abdominal or pelvic surgery c) thoracic surgery 3) neoplasms, esp. adenocarcinoma (5,6,24) a) lung cancer b) breast cancer c) ovarian cancer d) testicular cancer e) urologic malignancy f) gastrointestinal cancer - gastric cancer - pancreatic cancer g) advanced stage cancers, myeloproliferative disorders or myelodysplastic syndrome at highest risk [51] 4) pregnancy 5) pharmaceutical agents a) estrogens - oral contraceptives - hormone replacement therapy - tamoxifen b) megestrol (Megace) c) erythropoiesis-stimulating agents [40] d) chemotherapy [40] e) blood transfusion [40] 6) hypercoagulable states - factor V Leiden associated with 5-fold risk for 1st DVT but only 1.5-fold increased risk for recurrent DVT [5] 7) previous DVT 8) venulitis a) chemical - chemotherapy - radiocontrast - vasopressors b) infectious c) thromboangiitis obliterans (Buerger's disease) d) Behcet syndrome 9) varicose veins (RR=5.3) [79] 10) polycythemia 11) nephrotic syndrome 12) congestive heart failure 13) inflammatory bowel disease 14) advanced age 15) trauma (12.7) a) fractures of the spine, pelvis, femur, tibia b) injuries of the spinal cord, head & chest 16) obesity (3.9) 17) infection 18) QThrombosis (DVT/VTE risk calculator) Epidemiology: - men with higher risk of recurrent DVT than women (RR = 1.8-2.2) [33] Pathology: 1) calf DVT affecting the tibial, peroneal, gastrocnemius & soleal veins occurs more frequently than proximal DVT 2) 20% of calf DVTs propagate to proximal DVT affecting the popliteal, femoral & iliac veins 3) intrinsic pathway may play a role - FXI-ASO, siRNA reducing level of factor XI, prevents DVT after total knee arthroplasty better than enoxaparin (see FXI-ASO) 4) proximal DVTs involve superficial collateral veins Clinical manifestations: 1) Symptoms: a) acute onset of unilateral leg swelling b) exacerbation of pain with weight-bearing or ambulation c) pain described as tight, aching, deep or vice-like d) (see thrombophlebitis) 2) Signs: a) asymmetry - swelling - unilateral edema - begins in the foot & ankle - progresses upward depending upon extent of thrombosis - edema is pitting - an 'orange peel' consistency develops when venous return is severely inhibited - compare extremity circumference by measurement above & below the knee - calf circumference > 3 cm difference between lower legs b) tenderness c) extremity may be warm d) extremity may be red, cyanotic or discolored e) Homan's sign (unreliable) f) venous collaterals g) palpable cord h) fever 3) pain, edema, cyanosis, & arterial compromise suggest proximal DVT - massive proximal DVTs involve both deep veins & collateral veins - increased venous stasis, extravasation of venous fluid into the interstitium, painful swelling & violaceous changes - extremity may be cool & tender to palpation - also see complications - see phlegmasia cerulea dolens Laboratory: 1) D-dimer by ELISA or Liatest a) may be useful for assessment of DVT with low-moderate pretest probability [2,5] - patients with normal plasma D-dimer & low probability Well's rule or primary care rule do not need imaging studies [5,60] even if there are no alternative diagnoses [5] b) cutoff level 400 ng/mL - 500 ng/mL moderate risk patients; 1000 ng/mL low risk patients (risk from Wells prediction score) [45] c) 95% sensitive for proximal DVT - a negative test with low pre-test probability effectively rules out DVT d) 35% specificity - a positive test requires confirmation e) in combination with ultrasound [15] f) first test of choice in low risk patients [5] g) probably unnecessary for high-risk patients - proceed directly to ultrasound [45] h) may be useful for assessing risk of recurrent DVT after anticoagulation is stopped [5,19] - risk for recurrence after 1st unprovoked DVT forpatients with negative d-dimer not low enough tojustify anticoagulation in men, but may be in women [56] - 5-year risk for recurrence ~30% in men with unprovoked VTE, despite negative D-dimer testing [83] 2) fecal occult blood 3) complete blood count 4) serum chemistries a) prostate-specific antigen (PSA) for unprovoked DVT b) serum Ca+2 & serum albumin 5) Pap Smear for unprovoked DVT in women [62] 6) hypercoagulability workup a) not routinely indicated [5,75] - target testing of high-risk patients b) indications: 1] idiopathic DVT 2] recurrent DVT 3] family history of venous thromboembolism c) setting of thrombotic event, provoked vs unprovoked, provides greater prognostic information than does hypercoagulability workup [5] d) results of hypercoagulability workup generally do not influence treatment or duration of treatment [5] e) see criteria for hypercoagulability workup 7) monitor platelet count along with INR in patients treated with warfarin [61] 8) see ARUP consult [42] Radiology: 1) obtain imaging if Wells score (DVT) > 1 [5] 2) non-invasive tests a) ultrasound* [15,17] 1] Well's rule or primary care rule to predict need for ultrasound [32] - Well's rule not useful in inpatient setting [63] 2] criteria is failure of venous lumen to fully collapse under gentle pressure from ultrasound transducer/probe - non-compressibility of popliteal vein is consistent with upper leg DVT 3] 90% predictive value above knee 4] sensitivity 50-80% below knee, specificity 95% 5] pelvic veins not well visualized [7] 6] 82% sensitivity & specificity vs venography [7] for upper extremity DVT 7] negative results on whole-leg compression ultrasound in patients with low to intermediate risk of DVT (including post-partum women) is adequate to exclude a DVT [37,39] 8] negative results on proximal-leg compression ultrasound requires a repeated study [37] 9] operator-dependent 10] 2-point compression study inadequate to rule out DVT [57] - a patient with a positive d-dimer test & a negative 2-point compression study should undergo full lower extremity ultrasound within 1 week [57] b) impedance plethysmography (IPG) 1] 90% predictive value above knee 2] unreliable below knee c) I-fibrinogen scanning - 90% predictive for calf DVT 3) ascending contrast venography a) gold standard b) complications 1] DVT in 2-3% 2] hypersensitivity 3] uncomfortable for patient 4] renal insufficiency 5] congestive heart failure c) expensive 4) magnetic resonance* venography or direct thrombus imaging for pelvic & subclavian venous thrombosis [7] 5) chest X-ray (rule out lung carcinoma) 6) mammography for unprovoked DVT in women [62] 7) CT of abdomen not helpful for detection of cancer in unprovoked DVT [62] * negative ultrasound is sufficient to exclude clinically significant DVT & withhold anticoagulation [17] * see Follow-up in Management: section for ultrasound after completion of anticoagulation * resolution may be limited in patients who have had hip surgery [7] Differential diagnosis: 1) cellulitis with or without lymphangitis 2) compartment syndrome 3) muscle strain or rupture a) plantaris b) gastrocnemius 4) lymphedema 5) rupture of Baker's (popliteal) cyst 6) postphlebitic syndrome (chronic) 7) Well's rule or primary care rule used to assess likelihood of DVT prior to ultrasound [32] Complications: 1) pulmonary embolus (PE) a) 5-20% with calf DVT b) 30-50% with untreated proximal DVT - clinically silent PE not associated with risk for recurrent PE [29] c) superficial saphenous vein thrombosis rarely causes pulmonary embolism unless the thrombus propagates into the deep venous system at the greater saphenous- femoral vein junction 2) postphlebitic syndrome - compression stockings reduce incidence - 1 year of therapy non-inferior to 2 years [70] - 6 months after proximal DVT may be adequate [77] - below knee stockings as effective as thigh length after proximal DVT [38] - postphlebitic syndrome still develops in 1/3 of patients 3) heparin-induced thrombocytopenia 4) compartment syndrome - compresses arteries as well as veins 5) extension of isolated calf DVT to proximal DVT or PE occurs in 9% of patients not anticoagulated vs 3% anticoagulated patients, median time to proximal DVT 13 days,median time to PE 15 days [71] - risk higher when thrombus involves vein branches within the gastrocnemius or soleus muscle vs tibial veins or peroneal vein [71] Management: 1) general a) most important goal is prevention of pulmonary embolus b) negative ultrasound is sufficient to exclude clinically significant DVT & withhold anticoagulation [17] c) most patients can be managed at home without hospitalization 2) supportive a) bedrest b) elevation of extremity above heart c) graduated compression stocking - only if postphlebitic syndrome [69] (not for prophylaxis) - compression after DVT reduces residual vein obstruction & thus postphlebitic syndrome [81] - 6-24 months after 6 month treatment of proximal DVT [77]$ - one year of therapy non-inferior to 2 years [89] === anticoagulation === 1) anticoagulation for all patients with proximal DVT unless contraindication (see inferior vena cava (IVC) filter below) a) initiate therapy with LMW heparin, apixaban or rivaroxaban [5,25] 1] LMW heparin preferable to unfractionated heparin [5] 2] fondaparinux (Arixtra) is an alternative 3] continue LMW heparin for at least 5 days & until the INR is therapeutic (2.0-3.0) [5] (2 INR measurements at least 24 hours apart) 4] outpatient therapy is safe & effective in selected patients [5] 5] enoxaparin 1.5 mg/kg SQ QD or 1 mg/kg SQ BID [6] a] efficacy similar to heparin b] may be used as an outpatient c] no need to monitor coagulation tests 6] dalteparin 200 units/kg SQ QD 7] tinzaparin 175 units/kg SQ QD 8] fondaparinux a] < 50 kg (< 110 lbs) 5 mg SQ QD b] 50-100 kg (110-220 lbs) 7.5 mg SQ QD c] > 100 kg (> 220 lbs) 10 mg SQ QD [5] 9] thrombin inhibitor or danaparoid if thrombocytopenia that may be due to heparin-induced thrombocytopenia [5] - recent hospitalization, surgery, or known heparin exposure 10] initial management with LMW heparin can be done safely in the home [52] 11] use unfractionated heparin if emergent surgery or thrombolytic therapy is likely [5] - avoid if high risk of bleeding until bleeding risk resolves - see inferior vena cava (IVC) filter below 12] see special case of antiphospholipid antibody syndrome b) American College of Chest Physicians recommends use of newer anticoagulants (apixaban, dabigatran, edoxaban, rivaroxaban) vs warfarin in patients with or without cancer [5,69] - no difference in outcomes (recurrent DVT or all-cause mortality) in use of newer anticoagulants vs warfarin [43] - bleeding risk similar [76] - see special case of antiphospholipid antibody syndrome - duration of anticoagulation (same as warfarin) - 3 months for 1st provoked DVT or DVT with reversible cause(s) - 6 weeks if < 21 years [86] - 3 months of therapy superior to 6 weeks for isolated DVT [87] - indefinite if unprovoked - apixaban & rivaroxaban may be used as monotherapy - initial LMW heparin unnecessary [5] - treatment with apixaban for 1 year reduces recurrence of DVT [44] - apixaban 10 mg BID for 7 days followed by 5 mg BID for 6 months non inferior to warfarin [50] - rivaroxaban alone [31] - 15 mg PO BID for 3 weeks, followed by 20 mg PO QD - no need for bridging LMW heparin [74] - as good as SQ enoxaparin with conversion to warfarin - low risk of recurrent DVT or bleeding while treated with rivaroxaban [64] (low = 0 in study) - rivaroxaban with less major bleeding than LMW heparin/warfarin [67] - rivaroxaban & apixaban probably confer the lowest risks for major bleeding [54] - dabigatran requires initial LMW heparin [5,46] - non-inferior to warfarin - associated with higher risk of acute coronary syndrome than warfarin (risk 0.9% vs 0.2%) [46] - edoxaban requires initial LMW heparin [5] c) in cancer patients, initial anticoagulation with apixaban, rivaroxaban or LMW heparin [5] d) if warfarin is used, begin concurrently with heparin or LMW heparin 1] bolus, 10 mg QD for 1-2 days 2] begin at 2.5 mg QD 3] adjust dose to achieve INR of 2.0-3.0 - >= 5 days overlap with heparin/LMW heparin & until INR > 2 for 24 hours [5] 4] duration of warfarin (anticoagulation) therapy: a] 3-6 months for 1st occurrence with transient reversible risk factor [5,22,35] includes patients heterozygous for factor V Leiden mutation [5] - 6 weeks of therapy if provoked DVT in patient < 21 years [86] b] 6-12 months for 1st occurrence with thrombophilia or other chronic risk factor(s) c] indefinite therapy for idiopathic DVT & low risk of bleeding [5]; recurrent proximal DVT d] continue anticoagulation until catheter removed if catheter- associated DVT [5] e] repeat ultrasound prior to discontinuing anticoagulation to assess residual thrombosis f] long-term low-intensity anticoagulation for patients with idiopathic deep vein thrombosis: INR 1.5-2.0 (after 3 months of standard therapy) [10,11,25] g] risk of fatal pulmonary embolism after 6 month course of warfarin is low (< 1%) [23], especially if DVT was provoked h] results of thrombophilia testing generally do not influence duration of therapy, especially for patients with a single DVT resulting from major transient risk factor [5] 5] use LMW heparin rather than warfarin in patients with underlying malignancy based mostly on single trial [65] - LMW heparin & warfarin equivalent [65] - rivaroxaban associated with low recurrence of VTE but higher rate of hemorrhage compared with dalteparin [80] 6] avoid LMW heparin in patients with obesity or renal insufficiency 7] special considerations for women of child-bearing age - see anticoagulation & venous thromboembolism associated with pregnancy 8] if INR becomes subtherapeutic in the 1st month following pulmonary embolism, add LMW heparin until INR is stable in the therapeutic range [5] 9] falling platelet count & rapidly rising INR after the switch from heparin to warfarin is consistent with cancer-associated disseminated intravascular coagulation [61] - after excluding heparin-induced thrombocytopenia, discontinue warfarin, initiate a thrombin inhibitor & vitamin K, & search for an occult malignancy [61] e) American College of Chest Physicians recommends use aspirin after stopping anticoagulation [69] f) benefit of anticoagulation not supported by randomized clinical trials (see anticoagulation) [59] === procedures === 1) inferior vena cava (IVC) filter (i.e. Greenfield filter) a) proximal DVT in patient with contraindication to anticoagulation - major bleeding from arteriovenous malformation or other cause - anticoagulation once bleeding risk resolves b) recurrent thromboembolism despite adequate anticoagulation c) presence of a large, free-floating inferior vena cava thrombus d) recurrent embolism with pulmonary hypertension 2) thrombolytic therapy a) controversial b) IV or catheter-directed thrombolysis for large iliofemoral DVT [5,36] c) impaired venous drainage, severe edema, acute limb ischemia [5] d) catheter-directed thrombolysis associated with more complications than anticoagulation alone [53,78] e) MKSAP18 [5] downplays complications 3) surgical treatment (thrombectomy): threatened viable limb === isolated calf venous thrombosis === 1) isolated calf venous thrombosis a) anticoagulation for 3 months if symptomatic [5] b) if anticoagulation not given, serial noninvasive studies of the lower extremity should be done for 2 weeks to assess proximal extension of thrombus c) LMW heparin no better than placebo in reducing DVT extension to proximal veins, contralateral proximal DVT, or symptomatic pulmonary embolism in low-risk patients with isolated calf DVT, but does result in increased bleeding [72] d) anticoagulation prevents recurrent venous thromboembolism [85] - better outcomes with anticoagulation than serial ultrasound surveillance [85] === Prophylaxis, Duration of Anticoagulation, Activity, Follow-up === 1) Prophylaxis a) early ambulation b) stop offending agent c) pneumatic compression device (pcd) d) subcutaneous heparin e) warfarin f) B-vitamins to lower homocysteine of no benefit [20] g) vitamin E may be useful for primary prevention in women h) low dose aspirin 1] 100 mg QOD ineffective in preventing DVT in women > 45 years [21] 2] 100 mg QD reduces recurrent DVT in patients with unprovoked DVT who have received 6-18 months of warfarin [41] 3] rivaroxaban 10 or 20 mg QD more effective in preventing recurrent thromboembolism than aspirin with no difference in bleeding (RR= 1.5%, 1.2%, & 4.4%, respectively) [73] i) fondaparinux (Arixtra) is more effective than LMW heparin following orthopedic surgery [5] j) LMW heparin for at least 3-6 months for cancer patients with subsequent transition to warfarin if necessary [5] 2) duration of anticoagulation - 3-6 months for provoked DVT - extended anticoagulation for unprovoked proximal DVT - life-long anticoagulation for: - 2 or more spontaneous episodes of DVT - 1 spontaneous, life-threatening venous thromoembolism - 1 spontaneous venous thromboembolism in a patient with hypercoagulability - HERDOO2 score may be useful in women to assess need for long-term anticoagulation after unprovoked DVT 3) activity: a) hospitalization 1] elevate extremity 2] ambulate as tolerated b) discharge 1] gradually resume normal activities 2] avoid prolonged sitting or standing c) patients with low-risk PE may be treated at home or discharged early [69] d) avoid contact sports that exposes patient to risk of injury 4) follow-up: a) serial INR to monitor warfarin therapy b) follow-up ultrasound is not routinely performed after an acute DVT [27] - if follow-up ultrasound demonstrates non-obstructive residual thrombus 3-6 months after surgery or trauma, discontinue anticoagulation [88] c) if post-phlebitic syndrome is suspected, impedance plethysmography (ipg) or ultrasound can document the location & degree of venous insufficiency - graduated compression stocking if postphlebitic syndrome [69] thus postphlebitic syndrome [81] - 6-24 months after 6 month treatment of proximal DVT [77]$ - one year of compression non-inferior to 2 years [89] d) routine screening for potentially treatable carcinomas 1] breast examination & mammography 2] pap smear 3] colonoscopy vs sigmoidoscopy & air-contrast barium enema 4] prostate-specific antigen (PSA) 5] chest x-ray === Prognosis & Risk === 1) prognosis: a) distal & proximal deep venous thrombosis associated with similar outcomes in patients with cancer [90] b) risk factors for recurrent DVT [9,16] 1] residual thrombosis (2.4)* 2] idiopathic DVT (2,5) 3] hypercoagulable state (3.1) - heterozygousity for factor V Leiden mutation only confers 1.5 fold risk of recurrent DVT [5] 4] plasma d-dimer > 750 ng/mL (3.1)# [12,19,26] 5] male sex (3.6) [14] <31% vs 9%> c) risk or recurrence is lowest if 1st episode is provoked by surgery [30] d) 1/3 of patients with initial unprovoked venous thromboembolism who discontinue anticoagulation may experience recurrence within 10 years [84] e) good prognosis = age < 80 years, no significant comorbidity, stable vital signs - can be managed as outpatient [5] 2) risk for DVT is increased in relatives of index cases of unprovoked DVT (RR=2.4) [55] - risk increases with younger age of index case - for each younger year, risk increases by 3% - risk increase if more than one family member affected (RR=2.71) - risk increases if index case has factor V Leiden mutation or prothrombin G20210A gene variant (RR=4.42) [55] * relative risk in parenthesis # 3 weeks after cessation of anticoagulation $ knee-high compression stockings after proximal DVT? [77]

Interactions

disease interactions

Related

HERDOO2 Score hypercoagulability postphlebitic syndrome; post-thrombotic syndrome primary care rule for deep vein thrombosis prophylaxis for venous thromboembolism (VTE) pulmonary embolism (PE) QThrombosis (VTE/DVT risk calculator) venous thromboembolism (VTE) venous thromboembolism associated with pregnancy Wells clinical prediction rules for DVT

Specific

cerebral venous thrombosis; dural sinus thrombosis splanchnic vein thrombosis (SVT) upper extremity deep vein thrombosis (UEDVT)

General

thrombophlebitis (includes superficial venous thrombosis) venous thrombosis

References

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