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•  Proximal deep venous thrombosis (DVT): thrombosis of popliteal, femoral or iliac veins

(nb, “superficial” femoral vein part of deep venous system)

•  Pulmonary embolism (PE): thrombosis originating in venous system and embolizing to pulmonary arterial circulation; 1 case/1000 person y; 250,000/y (Archives 2003;163:1711)

Risk factors

•  Virchow’s triad for thrombogenesis

stasis: bed rest, inactivity, CHF, CVA w/in 3 mo, air travel >6 h (NEJM 2001;345:779)

injury to endothelium: trauma, surgery, prior DVT, inflammation

thrombophilia: APC resistance, protein C or S deficiency, APS, prothrombin gene mutation,↑ factor VIII, hyperhomocysteinemia, HIT, OCP, HRT, tamoxifen, raloxifene

•  Malignancy (12% of “idiopathic” DVT/PE)

•  History of thrombosis (greater risk of recurrent VTE than genetic thrombophilia)

•  Statin therapy ↓ risk (NEJM 2009;360:1851)

Clinical manifestations—DVT

•  Calf pain, swelling (>3 cm c/w unaffected side), venous distention, erythema, warmth, tenderness, palpable cord,  Homan’s sign (calf pain on dorsiflexion, seen in <5% of Pts), phlegmasia cerulea dolens: stagnant blood → edema, cyanosis, pain

•  50% of Pts with sx DVT have asx PE

Diagnostic studies—DVT

•  D-dimer: <500 helps r/o; ? use 1000 as threshold if low risk (Annals 2013;158:93)

•  Compression U/S >95% Se & Sp for sx DVT (lower for asx DVT); survey whole leg rather than just proximal if ≥mod prob (  JAMA 2010;303:438); venography rarely used

Figure 2-3 Approach to suspected DVT (Chest 2012;141:e351S)

Clinical manifestations—PE

•  Dyspnea (73%), pleuritic chest pain (66%), cough (37%), hemoptysis (13%)

•  ↑ RR (>70%), crackles (51%), ↑ HR (30%), fever, cyanosis, pleural friction rub, loud P2

•  Massive: syncope, HoTN, PEA; ↑ JVP, R-sided S3, Graham Steell (PR) murmur

Diagnostic studies—PE (NEJM 2010;363:266)

•  CXR (limited Se & Sp): 12% nl, atelectasis, effusion, ↑ hemidiaphragm, Hampton hump (wedge-shaped density abutting pleura); Westermark sign (avascularity distal to PE)

•  ECG (limited Se & Sp): sinus tachycardia, AF; signs of RV strain → RAD, P pulmonale, RBBB, SIQIIITIII & TWI V1–V4 (McGinn-White pattern, Chest 1997;111:537)

•  ABG: hypoxemia, hypocapnia, respiratory alkalosis, ↑ A-a gradient (Chest 1996;109:78) 18% w/ room air PaO2 85–105 mmHg, 6% w/ nl A-a gradient (Chest 1991;100:598)

•  D-dimer: high Se, poor Sp (~25%);  ELISA has >99% NPV and can be used to r/o PE in Pts w/ “unlikely” pretest prob. (  JAMA 2006;295:172)

•  Echocardiography: useful for risk stratification (RV dysfxn), but not dx (Se <50%)

•  V/Q scan: high Se (~98%), low Sp (~10%). Sp improves to 97% for high prob VQ. Use if pretest prob of PE high and CT not available or contraindicated. Can also exclude PE if low pretest prob, low prob VQ, but 4% false  (  JAMA 1990;263:2753).

•  CT angiography (CTA; see Radiology inserts): Se ~90% & Sp ~95% w/ MDCT (NEJM 2006;354:2317); PPV & NPV >95% if imaging concordant w/ clinical suspicion, ≤80% if discordant (∴ need to consider both); CT may also provide other dx

•  Lower extremity compression U/S shows DVT in ~9%, sparing CTA, but when added to CTA, does not Δ outcomes (Lancet 2008;371:1343)

•  Pulmonary angio: ? gold standard (morbidity 5%, mortality <0.5%), infrequently performed

•  MR angiography: Se 84% (segmental) to 100% (lobar) (Lancet 2002;359:1643); if add MR venography, Se 92%, Sp 96% (Annals 2010;152:434)

Figure 2-4 Approach to suspected PE using CTA

Workup for idiopathic VTE

•  Thrombophilia workup: ✓ if  FH, consider if age <50 y or on OCP/HRT. Send panel 2 wk after complete anticoagulation, as thrombus, heparin and warfarin Δ results. Nb, does not change management after 1st idiopathic DVT if plan for long- term anticoagulation (  JAMA 2005;293:2352; Blood 2008;112:4432; Am J Med 2008;121:458).

•  Malignancy workup: 12% Pts w/ “idiopathic” DVT/PE will have malignancy; age-appropriate screening adequate; avoid extensive w/u (NEJM 1998;338:1169)

Risk stratification for Pts with PE

•  Clinical: hypotension and/or tachycardia (~30% mortality), hypoxemia

•  CTA: RV / LV dimension ratio >0.9 (Circ 2004;110:3276)

•  Biomarkers: ↑ troponin (Circ 2002;106:1263), ↑ BNP (Circ 2003;107:1576) a/w ↑ mortality

•  Echocardiogram: RV dysfxn (controversial in absence of hypotension)

•  Simplified PE Severity Index: 0 RFs → 1.1% mort.; ≥1 → 8.9% mort (Archives 2010;170:1383) RFs: age >80 y; h/o cancer; h/o HF or lung disease; HR ≥110; SBP <100; SaO2 <90%

Treatment of VTE (Lancet 2012;379;1835; Chest 2012;141:e419S)

•  LE DVT: proximal → anticoagulate; distal: anticoagulate if severe sx or risk for extension, o/w may consider serial imaging (although if bleeding risk low, many would anticoagulate)

•  UE DVT: anticoagulate (same guidelines as LE; NEJM 2011;364:861). If catheter-associated, need not remove if catheter functional and ongoing need for catheter.

•  Superficial venous thrombosis: anticoagulate (esp. if extensive clot) as 10% experience thromboembolic event w/in 3 mo (Annals 2010;152:218)

•  Acute anticoagulation options (initiate immediately if high clinical suspicion!)

LMWH (eg, enoxaparin 1 mg/kg SC bid or dalteparin 200 IU/kg SC qd)

Preferred over UFH except: renal failure (CrCl <25), ? extreme obesity, hemodynamic instability or bleed risk (Cochrane 2004;CD001100)

No need to monitor anti-factor Xa unless concern re: dosing (eg, renal insuffic.)

Attractive option as outPt bridge to long-term oral anticoagulation

Fondaparinux: 5–10 mg SC qd (NEJM 2003;349:1695); use if HIT ; avoid if renal failure

IV UFH: 80 U/kg bolus → 18 U/kg/h → titrate to PTT 1.5–2.3 × cntl (eg, 60–85 sec)

Rivaroxaban: 15 mg bid (for 1st 3 wk)  LMWH followed by warfarin (NEJM 2010;363:2499 & 2012;366:1287); effect wears off w/in 24 h, but not easily immediately reversed

Direct thrombin inhibitors (eg, argatroban, lepirudin) used in HIT  Pts

•  Early ambulation

•  DVT & low-risk PE can be treated completely as outPt (Lancet 2011;378:41)

•  Thrombolysis (eg, TPA 100 mg over 2 h or wt-adjusted TNK bolus)

Use if PE a/w hemodynamic compromise (“massive PE”)

Consider if PE w/o hemodynamic compromise, but high-risk (“submassive PE,” eg, marked dyspnea, severe hypoxemia, RV dysfxn on echo, RV enlargement on CTA) and low bleed risk. Risk of ICH ~1% and no proven mortality benefit (NEJM 2002;347:1143; Cochrane 2006:CD004437).

Consider if extensive (eg, iliofemoral) acute DVT and catheter-directed Rx not available

•  Catheter-directed therapy (fibrinolytic & thrombus fragmentation/aspiration)

Consider if extensive vs. in all acute DVT as ↓ postthrombotic synd (Lancet 2012;379:31)

Consider if PE w/ hemodynamic compromise or high risk and not candidate for systemic fibrinolytic therapy or surgical thrombectomy (Circ 2011;124:2139)

•  Thrombectomy: if large, proximal PE + hemodynamic compromise + contra. to lysis;

consider in experienced ctr if large prox. PE + RV dysfxn (  J Thorac CV Surg 2005;129:1018)

•  IVC filter: if anticoagulation contraindication, failure or bleed, or ? ↓ CP reserve; temp. filter if risk time limited; adding filter to anticoagulation → PE ↓ 1/2, DVT ↑ 2×, no mort. diff. (NEJM1998;338:409; Circ 2005;112:416)

•  Long-term anticoagulation options

Warfarin (goal INR 2–3): start same day as heparin unless instability and ? need for lytic, catheter-based Rx or surgery; overlap ≥5 d w/ heparin & until INR ≥2 × ≥24 h

Rivaroxaban (after 15 mg bid for 1st 3 wk, then 20 mg qd)  warfarin (see refs above)

Dabigatran (NEJM 2009;361:2342) and idrabiotaparinux (weekly SC FXa inhib; Lancet 2012; 379:123) both appear  warfarin, but neither FDA approved

VTE a/w cancer: LMWH × 3–6 mo, then LMWH/warfarin indefinitely or until cancer cured (NEJM 2003;349:146); ✓ head CT for brain mets if melanoma, renal cell, thyroid, chorioCA

•  Duration of anticoagulation:

Superficial venous thrombosis: 4 wk

1st prox DVT or PE 2° reversible/time-limited risk factor or distal DVT: 3 mo

1st unprovoked prox DVT or PE: ≥3 mo, then reassess; if low bleed risk → indefinite Rx w/ warfarin; extended Rx w/ newer agents under study: c/w placebo apixaban (either 2.5 or 5 mg) ↓↓ VTE w/o ↑ major bleeding (NEJM 2013;368:699); rivaroxaban (20 mg qd) or dabigatran (150 mg bid) also ↓↓ VTE but ↑ major bleeding (NEJM 2010;363:2499 & 2013;368:709)

2nd VTE event: indefinite warfarin (NEJM 1997;336:393 & 2003;348:1425)

Can be guided by D-dimer testing at 1 & 3 mo (NEJM 2006;355:1780; Blood 2010;115:481)

After 6–18 mo of anticoag for unprovoked VTE, if decide to stop anticoag (eg, b/c of bleeding) ASA ↓ risk of recurrent VTE by 32% (NEJM 2012;366:1959 & 367:1979)

Complications & prognosis

•  Postthrombotic syndrome (25%): pain, swelling; ↓ with compression stockings × 3 mo

•  Recurrent VTE: 1%/y (after 1st VTE) to 5%/y (after recurrent VTE)

after only 6 mo of Rx: 5%/y & >10%/y, respectively

predictors: abnl D-dimer 1 month after d/c anticoag (NEJM 2006;355:1780);  U/S after 3 mo of anticoag (Annals 2002;137:955); thrombin generation >400 nM (  JAMA 2006;296:397)

•  Chronic thromboembolic PHT after acute PE ~3.8% (NEJM 2004;350:2257), consider thromboendarterectomy

•  Mortality: ~10% for DVT and ~10–15% for PE at 3–6 mo (Circ 2008;117:1711)