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Surgery_Schwartz. Bettmann M, et al. The durability of endovascular treatment of multisegment iliac occlusive dis-ease. J Vasc Surg. 2000;31(6):1178-1184. 134. Timaran CH, Stevens SL, Grandas OH, Freeman MB, Gold-man MH. Influence of hormone replacement therapy on the outcome of iliac angioplasty and stenting. J Vasc Surg. 2001;33(2 suppl):S85-S92. 135. Bosch JL, Hunink MG. Meta-analysis of the results of per-cutaneous transluminal angioplasty and stent placement for aortoiliac occlusive disease. Radiology. 1997;204(1):87-96. 136. Park KB, Do YS, Kim JH, et al. Stent placement for chronic iliac arterial occlusive disease: the results of 10 years experience in a single institution. Korean J Radiol. 2005;6(4):256-266. 137. Leville CD, Kashyap VS, Clair DG, et al. Endovascular man-agement of iliac artery occlusions: extending treatment to TransAtlantic Inter-Society Consensus class C and D patients. J Vasc Surg. 2006;43(1):32-39. 138. Tetteroo E, van der Graaf Y, Bosch JL, et al. Randomised com-parison of


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Surgery_Schwartz. extending treatment to TransAtlantic Inter-Society Consensus class C and D patients. J Vasc Surg. 2006;43(1):32-39. 138. Tetteroo E, van der Graaf Y, Bosch JL, et al. Randomised com-parison of primary stent placement versus primary angioplasty followed by selective stent placement in patients with iliac-artery occlusive disease. Dutch Iliac Stent Trial Study Group. Lancet. 1998;351(9110):1153-1159. 139. McDaniel MD, Cronenwett JL. Basic data related to the natu-ral history of intermittent claudication. Ann Vasc Surg. 1989; 3(3):273-277. 140. Leng GC, Papacosta O, Whincup P, et al. Femoral atheroscle-rosis in an older British population: prevalence and risk fac-tors. Atherosclerosis. 2000;152(1):167-174. 141. Schroll M, Munck O. Estimation of peripheral arteriosclerotic disease by ankle blood pressure measurements in a population study of 60-year-old men and women. J Chronic Dis. 1981; 34(6):261-269. 142. Stoffers HE, Rinkens PE, Kester AD, Kaiser V, Knottnerus JA. The prevalence of


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Surgery_Schwartz. blood pressure measurements in a population study of 60-year-old men and women. J Chronic Dis. 1981; 34(6):261-269. 142. Stoffers HE, Rinkens PE, Kester AD, Kaiser V, Knottnerus JA. The prevalence of asymptomatic and unrecognized periph-eral arterial occlusive disease. Int J Epidemiol. 1996;25(2): 282-290. 143. Koelemay MJ, den Hartog D, Prins MH, Kromhout JG, Legemate DA, Jacobs MJ. Diagnosis of arterial disease of the lower extremities with duplex ultrasonography. Br J Surg. 1996; 83(3):404-409. 144. Bah F, Bhimji SS. Peripheral arterial disease. StatPearls. Trea-sure Island (FL); 2018. 145. Ouriel K. Current status of thrombolysis for peripheral arterial occlusive disease. Ann Vasc Surg. 2002;16(6):797-804. 146. Ouriel K. Comparison of surgical and thrombolytic treatment of peripheral arterial disease. Rev Cardiovasc Med. 2002; 3(suppl 2):S7-S16. 147. Mahe G, Jaquinandi V. Diagnosis of lower limb peripheral artery disease [in French]. Presse Med. 2018;47(1):47-55. 148. Conte MS,


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Surgery_Schwartz. arterial disease. Rev Cardiovasc Med. 2002; 3(suppl 2):S7-S16. 147. Mahe G, Jaquinandi V. Diagnosis of lower limb peripheral artery disease [in French]. Presse Med. 2018;47(1):47-55. 148. Conte MS, Belkin M, Upchurch GR, Mannick JA, Whittemore AD, Donaldson MC. Impact of increasing comorbidity on infrainguinal reconstruction: a 20-year perspective. Ann Surg. 2001;233(3):445-452. 149. Johnston KW. Femoral and popliteal arteries: reanalysis of results of balloon angioplasty. Radiology. 1992;183(3):767-771. 150. Kok HK, Asadi H, Sheehan M, McGrath FP, Given MF, Lee MJ. Outcomes of infrapopliteal angioplasty for limb salvage based on the updated TASC II classification. Diagn Interv Radiol. 2017;23(5):360-364. 151. Lofberg AM, Karacagil S, Ljungman C, et al. Percutaneous transluminal angioplasty of the femoropopliteal arteries in limbs with chronic critical lower limb ischemia. J Vasc Surg. 2001;34(1):114-121. 152. Hunink MG, Wong JB, Donaldson MC, Meyerovitz MF, Har-rington DP. Patency


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Surgery_Schwartz. of the femoropopliteal arteries in limbs with chronic critical lower limb ischemia. J Vasc Surg. 2001;34(1):114-121. 152. Hunink MG, Wong JB, Donaldson MC, Meyerovitz MF, Har-rington DP. Patency results of percutaneous and surgical revas-cularization for femoropopliteal arterial disease. Med Decis Making. 1994;14(1):71-81. 153. Varty K, Bolia A, Naylor AR, Bell PR, London NJ. Infrapopli-teal percutaneous transluminal angioplasty: a safe and success-ful procedure. Eur J Vasc Endovasc Surg. 1995;9(3):341-345. 154. Bolia A, Sayers RD, Thompson MM, Bell PR. Subinti-mal and intraluminal recanalisation of occluded crural Brunicardi_Ch23_p0897-p0980.indd 97827/02/19 4:15 PM 979ARTERIAL DISEASECHAPTER 23arteries by percutaneous balloon angioplasty. Eur J Vasc Surg. 1994;8(2):214-219. 155. Lipsitz EC, Ohki T, Veith FJ, et al. Does subintimal angio-plasty have a role in the treatment of severe lower extremity ischemia? J Vasc Surg. 2003;37(2):386-391. 156. Treiman GS, Whiting JH, Treiman


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Surgery_Schwartz. EC, Ohki T, Veith FJ, et al. Does subintimal angio-plasty have a role in the treatment of severe lower extremity ischemia? J Vasc Surg. 2003;37(2):386-391. 156. Treiman GS, Whiting JH, Treiman RL, McNamara RM, Ashrafi A. Treatment of limb-threatening ischemia with percu-taneous intentional extraluminal recanalization: a preliminary evaluation. J Vasc Surg. 2003;38(1):29-35. 157. Ingle H, Nasim A, Bolia A, et al. Subintimal angioplasty of isolated infragenicular vessels in lower limb ischemia: long-term results. J Endovasc Ther. 2002;9(4):411-416. 158. Becquemin JP, Favre JP, Marzelle J, Nemoz C, Corsin C, Leizorovicz A. Systematic versus selective stent placement after superficial femoral artery balloon angioplasty: a mul-ticenter prospective randomized study. J Vasc Surg. 2003; 37(3):487-494. 159. Gray BH, Sullivan TM, Childs MB, Young JR, Olin JW. High incidence of restenosis/reocclusion of stents in the percutaneous treatment of long-segment superficial femo-ral artery disease


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Surgery_Schwartz. BH, Sullivan TM, Childs MB, Young JR, Olin JW. High incidence of restenosis/reocclusion of stents in the percutaneous treatment of long-segment superficial femo-ral artery disease after suboptimal angioplasty. J Vasc Surg. 1997;25(1):74-83. 160. Mewissen MW. Self-expanding nitinol stents in the femoro-popliteal segment: technique and mid-term results. Tech Vasc Interv Radiol. 2004;7(1):2-5. 161. Laird JR. Interventional options in SFA. Endovascular Today. 2004;(supp):9-12. 162. Ansel GM, Silver MJ, Botti CF Jr, et al. Functional and clini-cal outcomes of nitinol stenting with and without abciximab for complex superficial femoral artery disease: a randomized trial. Catheter Cardiovasc Interv. 2006;67(2):288-297. 163. Duda SH, Poerner TC, Wiesinger B, et al. Drug-eluting stents: potential applications for peripheral arterial occlusive disease. J Vasc Interv Radiol. 2003;14(3):291-301. 164. Feiring AJ, Krahn M, Nelson L, Wesolowski A, Eastwood D, Szabo A. Preventing leg amputations in


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Surgery_Schwartz. applications for peripheral arterial occlusive disease. J Vasc Interv Radiol. 2003;14(3):291-301. 164. Feiring AJ, Krahn M, Nelson L, Wesolowski A, Eastwood D, Szabo A. Preventing leg amputations in critical limb ischemia with below-the-knee drug-eluting stents: the PaRADISE (PRe-venting Amputations using Drug eluting StEnts) trial. J Am Coll Cardiol. 2010;55(15):1580-1589. 165. Bauermeister G. Endovascular stent-grafting in the treatment of superficial femoral artery occlusive disease. J Endovasc Ther. 2001;8(3):315-320. 166. Kedora J, Hohmann S, Garrett W, Munschaur C, Theune B, Gable D. Randomized comparison of percutaneous Viabahn stent grafts vs prosthetic femoral-popliteal bypass in the treat-ment of superficial femoral arterial occlusive disease. J Vasc Surg. 2007;45(1):10-16; discussion 16. 167. McQuade K, Gable D, Pearl G, Theune B, Black S. Four-year randomized prospective comparison of percutaneous ePTFE/nitinol self-expanding stent graft versus prosthetic femoral-popliteal


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Surgery_Schwartz. 16. 167. McQuade K, Gable D, Pearl G, Theune B, Black S. Four-year randomized prospective comparison of percutaneous ePTFE/nitinol self-expanding stent graft versus prosthetic femoral-popliteal bypass in the treatment of superficial femoral artery occlusive disease. J Vasc Surg. 2010;52(3):584-590; discus-sion 590-581, 591 e581-591 e587. 168. Ramaiah V, Gammon R, Kiesz S, et al. Midterm outcomes from the TALON Registry: treating peripherals with SilverHawk: outcomes collection. J Endovasc Ther. 2006;13(5):592-602. 169. Franzone A, Ferrone M, Carotenuto G, et al. The role of ather-ectomy in the treatment of lower extremity peripheral artery disease. BMC Surg. 2012;12(suppl 1):S13. 170. Scheinert D, Laird JR Jr, Schroder M, Steinkamp H, Balzer JO, Biamino G. Excimer laser-assisted recanalization of long, chronic superficial femoral artery occlusions. J Endovasc Ther. 2001;8(2):156-166. 171. Steinkamp HJ, Rademaker J, Wissgott C, et al. Percutane-ous transluminal laser angioplasty versus


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Surgery_Schwartz. of long, chronic superficial femoral artery occlusions. J Endovasc Ther. 2001;8(2):156-166. 171. Steinkamp HJ, Rademaker J, Wissgott C, et al. Percutane-ous transluminal laser angioplasty versus balloon dilation for treatment of popliteal artery occlusions. J Endovasc Ther. 2002;9(6):882-888. 172. Laird JR, Reiser C, Biamino G, Zeller T. Excimer laser assisted angioplasty for the treatment of critical limb ischemia. J Car-diovasc Surg (Torino). 2004;45(3):239-248. 173. Dave RM, Patlola R, Kollmeyer K, et al. Excimer laser recana-lization of femoropopliteal lesions and 1-year patency: results of the CELLO registry. J Endovasc Ther. 2009;16(6):665-675. 174. Clark TW, Groffsky JL, Soulen MC. Predictors of long-term patency after femoropopliteal angioplasty: results from the STAR registry. J Vasc Interv Radiol. 2001;12(8):923-933. 175. Axisa B, Fishwick G, Bolia A, et al. Complications follow-ing peripheral angioplasty. Ann R Coll Surg Engl. 2002;84(1): 39-42. 176. Yilmaz S, Sindel T,


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Surgery_Schwartz. J Vasc Interv Radiol. 2001;12(8):923-933. 175. Axisa B, Fishwick G, Bolia A, et al. Complications follow-ing peripheral angioplasty. Ann R Coll Surg Engl. 2002;84(1): 39-42. 176. Yilmaz S, Sindel T, Yegin A, Luleci E. Subintimal angioplasty of long superficial femoral artery occlusions. J Vasc Interv Radiol. 2003;14(8):997-1010. 177. Desgranges P, Boufi M, Lapeyre M, et al. Subintimal angio-plasty: feasible and durable. Eur J Vasc Endovasc Surg. 2004; 28(2):138-141. 178. Fava M, Loyola S, Polydorou A, Papapavlou P, Mendiz O, Joye JD. Cryoplasty for femoropopliteal arterial disease: late angiographic results of initial human experience. J Vasc Interv Radiol. 2004;15(11):1239-1243. 179. Jahnke T, Andresen R, Muller-Hulsbeck S, et al. Hemobahn stent-grafts for treatment of femoropopliteal arterial obstruc-tions: midterm results of a prospective trial. J Vasc Interv Radiol. 2003;14(1):41-51. 180. Grubnic S, Heenan SD, Buckenham TM, Belli AM. Evalu-ation of the pullback atherectomy


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Surgery_Schwartz. arterial obstruc-tions: midterm results of a prospective trial. J Vasc Interv Radiol. 2003;14(1):41-51. 180. Grubnic S, Heenan SD, Buckenham TM, Belli AM. Evalu-ation of the pullback atherectomy catheter in the treatment of lower limb vascular disease. Cardiovasc Intervent Radiol. 1996;19(3):152-159. 181. Savader SJ, Venbrux AC, Mitchell SE, et al. Percutaneous transluminal atherectomy of the superficial femoral and pop-liteal arteries: long-term results in 48 patients. Cardiovasc Intervent Radiol. 1994;17(6):312-318. 182. Albers M, Battistella VM, Romiti M, Rodrigues AA, Pereira CA. Meta-analysis of polytetrafluoroethylene bypass grafts to infrapopliteal arteries. J Vasc Surg. 2003;37(6):1263-1269. 183. Hamsho A, Nott D, Harris PL. Prospective randomised trial of distal arteriovenous fistula as an adjunct to femoro-infrap-opliteal PTFE bypass. Eur J Vasc Endovasc Surg. 1999;17(3): 197-201. 184. Davies AH, Hawdon AJ, Sydes MR, Thompson SG. Is duplex surveillance of value after leg


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Surgery_Schwartz. fistula as an adjunct to femoro-infrap-opliteal PTFE bypass. Eur J Vasc Endovasc Surg. 1999;17(3): 197-201. 184. Davies AH, Hawdon AJ, Sydes MR, Thompson SG. Is duplex surveillance of value after leg vein bypass grafting? Princi-pal results of the Vein Graft Surveillance Randomised Trial (VGST). Circulation. 2005;112(13):1985-1991. 185. Baldwin ZK, Pearce BJ, Curi MA, et al. Limb salvage after infrainguinal bypass graft failure. J Vasc Surg. 2004;39(5): 951-957. 186. Stone PA, Flaherty SK, Aburahma AF, et al. Factors affect-ing perioperative mortality and wound-related complications following major lower extremity amputations. Ann Vasc Surg. 2006;20(2):209-216. 187. Holzenbein TJ, Pomposelli FB Jr, Miller A, et al. The upper arm basilic-cephalic loop for distal bypass grafting: techni-cal considerations and follow-up. J Vasc Surg. 1995;21(4): 586-592; discussion 592-594. 188. Dardik H, Wengerter K, Qin F, et al. Comparative decades of experience with glutaraldehyde-tanned human


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Surgery_Schwartz. considerations and follow-up. J Vasc Surg. 1995;21(4): 586-592; discussion 592-594. 188. Dardik H, Wengerter K, Qin F, et al. Comparative decades of experience with glutaraldehyde-tanned human umbilical cord vein graft for lower limb revascularization: an analysis of 1275 cases. J Vasc Surg. 2002;35(1):64-71. 189. Johnson WC, Lee KK. A comparative evaluation of polytet-rafluoroethylene, umbilical vein, and saphenous vein bypass grafts for femoral-popliteal above-knee revascularization: a prospective randomized Department of Veterans Affairs coop-erative study. J Vasc Surg. 2000;32(2):268-277. 190. Fahner PJ, Idu MM, van Gulik TM, Legemate DA. Sys-tematic review of preservation methods and clinical Brunicardi_Ch23_p0897-p0980.indd 97927/02/19 4:15 PM 980SPECIFIC CONSIDERATIONSPART IIoutcome of infrainguinal vascular allografts. J Vasc Surg. 2006;44(3):518-524. 191. Gupta SK, Veith FJ, Kram HB, Wengerter KR. Prospective, randomized comparison of ringed and nonringed


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Surgery_Schwartz. of infrainguinal vascular allografts. J Vasc Surg. 2006;44(3):518-524. 191. Gupta SK, Veith FJ, Kram HB, Wengerter KR. Prospective, randomized comparison of ringed and nonringed polytetra-fluoroethylene femoropopliteal bypass grafts: a preliminary report. J Vasc Surg. 1991;13(1):163-172. 192. Stonebridge PA, Prescott RJ, Ruckley CV. Randomized trial comparing infrainguinal polytetrafluoroethylene bypass graft-ing with and without vein interposition cuff at the distal anas-tomosis. The Joint Vascular Research Group. J Vasc Surg. 1997;26(4):543-550. 193. Klinkert P, van Dijk PJ, Breslau PJ. Polytetrafluoroethylene femorotibial bypass grafting: 5-year patency and limb salvage. Ann Vasc Surg. 2003;17(5):486-491. 194. Panneton JM, Hollier LH, Hofer JM. Multicenter randomized prospective trial comparing a pre-cuffed polytetrafluoroethyl-ene graft to a vein cuffed polytetrafluoroethylene graft for infra-genicular arterial bypass. Ann Vasc Surg. 2004;18(2):199-206. 195. Bellosta R, Luzzani L,


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Surgery_Schwartz. a pre-cuffed polytetrafluoroethyl-ene graft to a vein cuffed polytetrafluoroethylene graft for infra-genicular arterial bypass. Ann Vasc Surg. 2004;18(2):199-206. 195. Bellosta R, Luzzani L, Carugati C, Melloni C, Sarcina A. Which distal anastomosis should be used in PTFE femoro-tibial bypass? J Cardiovasc Surg (Torino). 2005;46(5):499-503. 196. Begovac PC, Thomson RC, Fisher JL, Hughson A, Gallhagen A. Improvements in GORE-TEX vascular graft performance by Carmeda BioActive surface heparin immobilization. Eur J Vasc Endovasc Surg. 2003;25(5):432-437. 197. Devine C, Hons B, McCollum C. Heparin-bonded Dacron or polytetrafluoroethylene for femoropopliteal bypass grafting: a multicenter trial. J Vasc Surg. 2001;33(3):533-539. 198. Walluscheck KP, Bierkandt S, Brandt M, Cremer J. Infrain-guinal ePTFE vascular graft with bioactive surface heparin bonding. First clinical results. J Cardiovasc Surg (Torino). 2005;46(4):425-430. 199. Hunink MG, Donaldson MC, Meyerovitz MF, et al. Risks and


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Surgery_Schwartz. ePTFE vascular graft with bioactive surface heparin bonding. First clinical results. J Cardiovasc Surg (Torino). 2005;46(4):425-430. 199. Hunink MG, Donaldson MC, Meyerovitz MF, et al. Risks and benefits of femoropopliteal percutaneous balloon angioplasty. J Vasc Surg. 1993;17(1):183-192; discussion 192-194. 200. Dua A, Koprowski S, Upchurch G, Lee CJ, Desai SS. Pro-gressive shortfall in open aneurysm experience for vascular surgery trainees with the impact of fenestrated and branched endovascular technology. J Vasc Surg. 2017;65(1):257-261. 201. Ferreira M, Lanziotti L, Monteiro M, et al. Superficial femo-ral artery recanalization with self-expanding nitinol stents: long-term follow-up results. Eur J Vasc Endovasc Surg. 2007; 34(6):702-708. 202. Schillinger M, Sabeti S, Dick P, et al. Sustained benefit at 2 years of primary femoropopliteal stenting compared with balloon angioplasty with optional stenting. Circulation. 2007;115(21):2745-2749. 203. Bosiers M, Deloose K, Verbist J,


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Surgery_Schwartz. Sustained benefit at 2 years of primary femoropopliteal stenting compared with balloon angioplasty with optional stenting. Circulation. 2007;115(21):2745-2749. 203. Bosiers M, Deloose K, Verbist J, Peeters P. Nitinol stenting for treatment of “below-the-knee” critical limb ischemia: 1-year angiographic outcome after Xpert stent implantation. J Car-diovasc Surg (Torino). 2007;48(4):455-461. 204. Kickuth R, Keo HH, Triller J, Ludwig K, Do DD. Initial clinical experience with the 4-F self-expanding XPERT stent system for infrapopliteal treatment of patients with severe claudication and critical limb ischemia. J Vasc Interv Radiol. 2007;18(6):703-708. 205. Wolf GL, Wilson SE, Cross AP, Deupree RH, Stason WB. Sur-gery or balloon angioplasty for peripheral vascular disease: a randomized clinical trial. Principal investigators and their Associates of Veterans Administration Cooperative Study Number 199. J Vasc Interv Radiol. 1993;4(5):639-648. 206. Adam DJ, Beard JD, Cleveland T, et al.


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Surgery_Schwartz. trial. Principal investigators and their Associates of Veterans Administration Cooperative Study Number 199. J Vasc Interv Radiol. 1993;4(5):639-648. 206. Adam DJ, Beard JD, Cleveland T, et al. Bypass versus angio-plasty in severe ischaemia of the leg (BASIL): multicentre, ran-domised controlled trial. Lancet. 2005;366(9501):1925-1934. 207. Nolan B, Finlayson S, Tosteson A, Powell R, Cronenwett J. The treatment of disabling intermittent claudication in patients with superficial femoral artery occlusive disease--decision analysis. J Vasc Surg. 2007;45(6):1179-1184. 208. Maffei S, Di Renzo M, Bova G, Auteri A, Pasqui AL. Takayasu’s arteritis: a review of the literature. Intern Emerg Med. 2006;1(2):105-112. 209. Baxter BT. Heritable diseases of the blood vessels. Cardiovasc Pathol. 2005;14(4):185-188. 210. Cikrit DF, Glover JR, Dalsing MC, Silver D. The Ehlers-Danlos specter revisited. Vasc Endovascular Surg. 2002; 36(3):213-217. 211. Ho NC, Tran JR, Bektas A. Marfan’s syndrome. Lancet.


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Surgery_Schwartz. DF, Glover JR, Dalsing MC, Silver D. The Ehlers-Danlos specter revisited. Vasc Endovascular Surg. 2002; 36(3):213-217. 211. Ho NC, Tran JR, Bektas A. Marfan’s syndrome. Lancet. 2005;366(9501):1978-1981. 212. Davies JE, Sundt TM. Surgery insight: the dilated ascending aorta—indications for surgical intervention. Nat Clin Pract Cardiovasc Med. 2007;4(6):330-339. 213. London NJ, Srinivasan R, Naylor AR, et al. Subintimal angio-plasty of femoropopliteal artery occlusions: the long-term results. Eur J Vasc Surg. 1994;8(2):148-155. 214. Chassaing N, Martin L, Calvas P, Le Bert M, Hovnanian A. Pseudoxanthoma elasticum: a clinical, pathophysiological and genetic update including 11 novel ABCC6 mutations. J Med Genet. 2005;42(12):881-892. 215. Yeung RS. Pathogenesis and treatment of Kawasaki’s disease. Curr Opin Rheumatol. 2005;17(5):617-623. 216. Greco A, De Virgilio A, Ralli M, et al. Behcet’s disease: new insights into pathophysiology, clinical features and treatment options. Autoimmun Rev.


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Surgery_Schwartz. Curr Opin Rheumatol. 2005;17(5):617-623. 216. Greco A, De Virgilio A, Ralli M, et al. Behcet’s disease: new insights into pathophysiology, clinical features and treatment options. Autoimmun Rev. 2018;17(6):567-575. 217. Uygunoglu U, Siva A. Behcet’s syndrome and nervous system involvement. Curr Neurol Neurosci Rep. 2018;18(7):35. 218. Muhammad JS, Ishaq M, Ahmed K. Genetics and epigenetics pathogenesis of Behcet’s syndrome. Curr Rheumatol Rev. 2018. 219. Stanton M, Bhimji SS. Polyarteritis nodosa. StatPearls. Trea-sure Island (FL); 2018. 220. Temprano KK. A review of Raynaud’s disease. Mo Med. 2016; 113(2):123-126. 221. Hinojosa CA, Anaya-Ayala JE, Bermudez-Serrato K, et al. Surgical interventions for organ and limb ischemia associ-ated with primary and secondary antiphospholipid antibody syndrome with arterial involvement. Vasc Endovascular Surg. 2017;51(8):550-554. 222. Narula N, Kadian-Dodov D, Olin JW. Fibromuscular dyspla-sia: contemporary concepts and future directions. Prog


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Surgery_Schwartz. syndrome with arterial involvement. Vasc Endovascular Surg. 2017;51(8):550-554. 222. Narula N, Kadian-Dodov D, Olin JW. Fibromuscular dyspla-sia: contemporary concepts and future directions. Prog Car-diovasc Dis. 2018;60(6):580-585. 223. Baradhi KM, Bream P. Fibromuscular dysplasia. StatPearls. Treasure Island (FL); 2018. 224. Li S, King BN, Velasco N, Kumar Y, Gupta N. Cystic adven-titial disease-case series and review of literature. Ann Transl Med. 2017;5(16):327. 225. Lejay A, Ohana M, Lee JT, et al. Popliteal artery entrapment syndrome. J Cardiovasc Surg (Torino). 2014;55(2 suppl 1): 225-237. 226. Gokkus K, Sagtas E, Bakalim T, Taskaya E, Aydin AT. Pop-liteal entrapment syndrome. A systematic review of the lit-erature and case presentation. Muscles Ligaments Tendons J. 2014;4(2):141-148. 227. Rivera-Chavarria IJ, Brenes-Gutierrez JD. Thromboangiitis obliterans (Buerger’s disease). Ann Med Surg (Lond). 2016; 7:79-82. 228. Sugimoto M, Miyachi H, Morimae H, et al. Fate of ischemic


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Surgery_Schwartz. IJ, Brenes-Gutierrez JD. Thromboangiitis obliterans (Buerger’s disease). Ann Med Surg (Lond). 2016; 7:79-82. 228. Sugimoto M, Miyachi H, Morimae H, et al. Fate of ischemic limbs in patients with Buerger’s disease based on our 30-year experience: does smoking have a definitive impact on the late loss of limbs? Surg Today. 2015;45(4):466-470. 229. Mills JL Sr. Buerger’s disease in the 21st century: diagnosis, clinical features, and therapy. Semin Vasc Surg. 2003;16(3): 179-189.Brunicardi_Ch23_p0897-p0980.indd 98027/02/19 4:15 PM


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Surgery_Schwartz. Venous and Lymphatic DiseaseAtish Chopra, Timothy K. Liem, and Gregory L. Moneta 24chapterVENOUS ANATOMYVeins are part of a dynamic and complex system that returns low-nutrient deoxygenated blood to the heart. Venous blood flow is dependent on multiple factors such as gravity, venous valves, the cardiac and respiratory cycles, blood volume, and the calf muscle and feet pumps. Alterations in the intricate balance of these factors can result in venous pathology.Structure of VeinsVeins are thin-walled, highly distensible, and collapsible. Their structure specifically supports the primary functions of veins to transport blood toward the heart and serve as a reservoir to prevent intravascular volume overload.The venous intima is composed of a nonthrombogenic endothelium with an underlying basement membrane and an elastic lamina. The endothelium produces endothelium-derived relaxing factors such as nitric oxide and prostacy-clin, which help maintain a nonthrombogenic surface through


Surgery_Schwartz

Surgery_Schwartz. basement membrane and an elastic lamina. The endothelium produces endothelium-derived relaxing factors such as nitric oxide and prostacy-clin, which help maintain a nonthrombogenic surface through inhibition of platelet aggregation and promotion of platelet disaggregation.1 The capacitance function of veins is facili-tated by circumferential rings of elastic tissue, and smooth muscle located in the media of the vein allows for changes in vein caliber with minimal changes in venous pressure. The adventitia is most prominent in large veins and consists of collagen, elastic fibers, and fibroblasts. When a vein is maxi-mally distended, its diameter may be several times greater than that in the supine position.In the axial veins, unidirectional blood flow is achieved with multiple venous valves. The inferior vena cava (IVC), common iliac veins, portal venous system, and cranial sinuses are valveless. In the axial veins, valves are more numerous distally in the extremities than proximally.


Surgery_Schwartz

Surgery_Schwartz. The inferior vena cava (IVC), common iliac veins, portal venous system, and cranial sinuses are valveless. In the axial veins, valves are more numerous distally in the extremities than proximally. Each valve consists of two thin cusps of a fine connective tissue skeleton covered by endothelium. Venous valves close in response to cephalad-to-caudal blood flow at a velocity of at least 30 cm/s.2Lower Extremity VeinsLower extremity veins are divided into superficial, deep, and perforating veins. The superficial venous system lies above the uppermost fascial layer of the leg and thigh and consists of the great saphenous vein (GSV) and small saphenous vein (SSV) and their tributaries. The GSV originates from the dorsal pedal venous arch and courses cephalad and medially, anterior to the medial malleolus, entering the common femoral vein approxi-mately 4 cm inferior and lateral to the pubic tubercle. The saphe-nous nerve accompanies the GSV medially from the ankle to the level of the knee


Surgery_Schwartz

Surgery_Schwartz. malleolus, entering the common femoral vein approxi-mately 4 cm inferior and lateral to the pubic tubercle. The saphe-nous nerve accompanies the GSV medially from the ankle to the level of the knee and supplies cutaneous sensation to the medial leg and ankle. The SSV originates laterally from the dorsal pedal venous arch and courses cephalad in the posterior calf. Most often, it penetrates the popliteal fossa, between the medial and lateral heads of the gastrocnemius muscle, to join the popliteal vein. The termination of the SSV may be quite vari-able, however, with a proximal extension of the SSV (the vein of Giacomini) connecting with the deep femoral vein or GSV. The sural nerve accompanies the SSV laterally along its course and supplies cutaneous sensation to the lateral malleolar region.The deep veins follow the course of major arteries in the extremities. In the lower leg, paired veins parallel the course of the anterior tibial, posterior tibial, and peroneal arteries, to join


Surgery_Schwartz

Surgery_Schwartz. deep veins follow the course of major arteries in the extremities. In the lower leg, paired veins parallel the course of the anterior tibial, posterior tibial, and peroneal arteries, to join behind the knee forming the popliteal vein. Venous bridges con-nect the paired axial tibial veins in the lower leg. The popliteal vein continues through the adductor hiatus to become the femo-ral vein. In the proximal thigh, the femoral vein joins with the deep femoral vein to form the common femoral vein, becoming the external iliac vein at the inguinal ligament.Multiple perforator veins traverse the deep fascia to connect the superficial and deep venous systems. Potentially clinically important perforator veins are the posterior tibial and paratibial perforators (formerly known as the Cockett and Boyd perforators, respectively). The posterior tibial perforator veins drain the medial lower leg and are relatively constant. They Venous Anatomy981Structure of Veins / 981Lower Extremity Veins /


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Surgery_Schwartz. Boyd perforators, respectively). The posterior tibial perforator veins drain the medial lower leg and are relatively constant. They Venous Anatomy981Structure of Veins / 981Lower Extremity Veins / 981Upper Extremity Veins / 982Evaluation of the Venous System982Clinical Evaluation / 982Venous Thromboembolism984Epidemiology / 984Risk Factors / 984Diagnosis / 986Treatment / 987Prophylaxis / 992Other Venous Thrombotic Disorders994Superficial Vein Thrombophlebitis / 994Upper Extremity Vein Thrombosis / 995Mesenteric Vein Thrombosis / 996Varicose Veins996Chronic Venous Insufficiency997Evaluation of Venous Insufficiency / 997Lymphedema1001Pathophysiology / 1001Clinical Diagnosis / 1001Radiologic Diagnosis / 1002Management / 1002Summary1003Brunicardi_Ch24_p0981-p1008.indd 98122/02/19 3:00 PM 982connect the posterior accessory GSV (formerly known as the posterior arch vein, a tributary to the GSV) and the posterior tibial vein. They may become varicose or incompetent in venous


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Surgery_Schwartz. 3:00 PM 982connect the posterior accessory GSV (formerly known as the posterior arch vein, a tributary to the GSV) and the posterior tibial vein. They may become varicose or incompetent in venous insufficiency states. The posterior accessory GSV has relevance as it represents a connection of the three ankle perforating veins, which are likely of particular importance in the development of a venous stasis ulcers. The paratibial perforator veins connect the GSV to the deep veins approximately 10 cm below the knee and 1 to 2 cm medial to the tibia. Additional perforators in the thigh are known as the perforators of the femoral canal (also known as Hunter’s and Dodd’s perforators).Venous sinuses are thin-walled, large veins located within the substance of the soleus and gastrocnemius muscles. These sinuses are valveless and are linked by valved, small venous channels that prevent reflux. A large amount of blood can be stored in the venous sinuses before draining into the posterior


Surgery_Schwartz

Surgery_Schwartz. These sinuses are valveless and are linked by valved, small venous channels that prevent reflux. A large amount of blood can be stored in the venous sinuses before draining into the posterior tibial and peroneal veins. With each contraction of the calf muscle bed, blood is pumped out through the venous channels into the main conduit veins to return to the heart.Upper Extremity VeinsAs in the lower extremity, there are deep and superficial veins in the upper extremity. Deep digital veins form the palmar venous arches of the hand and empty into the paired radial and ulnar veins. These follow the named arteries in the arm and are known as the venae comitantes. They become the brachial veins most often near the antecubital fossa and then combine to contrib-ute to forming the axillary vein. Superficial veins of the upper extremity are the cephalic and basilic veins and their tributaries. The cephalic vein originates at the lateral wrist and courses over the lateral ventral surface of the


Surgery_Schwartz

Surgery_Schwartz. veins of the upper extremity are the cephalic and basilic veins and their tributaries. The cephalic vein originates at the lateral wrist and courses over the lateral ventral surface of the forearm. In the upper arm, the cephalic vein terminates in the infraclavicular fossa, piercing the clavipectoral fascia to empty into the axillary vein. The basilic vein runs medially along the forearm and penetrates the deep fascia as it courses past the elbow in the upper arm. It then joins with the deep brachial veins to become the axil-lary vein, a landmark for identification of the axillary vein. The median antecubital vein joins the cephalic and the basilic veins on the ventral surface of the elbow.The axillary vein becomes the subclavian vein at the lat-eral border of the first rib. At the medial border of the scalenus anterior muscle, the subclavian vein joins with the internal jugu-lar vein to become the brachiocephalic vein, with the subclavian vein coursing anterior to the scalenus


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Surgery_Schwartz. medial border of the scalenus anterior muscle, the subclavian vein joins with the internal jugu-lar vein to become the brachiocephalic vein, with the subclavian vein coursing anterior to the scalenus anterior muscle. The left and right brachiocephalic veins join to become the superior vena cava, which empties into the right atrium.EVALUATION OF THE VENOUS SYSTEMClinical EvaluationEvaluation of the venous system begins with a detailed history and physical examination. Risk factors for acute and chronic venous disease are identified. They include increased age, his-tory of venous thromboembolism (VTE), malignancy, trauma and spinal cord injury, hospitalization and immobilization, obe-sity, nephrotic syndrome, pregnancy, recent postpartum state, oral contraceptive use or hormone replacement therapy, vari-cose veins, and hypercoagulable states, as well as the postopera-tive state. Venous pathology is often, but not always, associated with visible or palpable signs that can be identified


Surgery_Schwartz

Surgery_Schwartz. therapy, vari-cose veins, and hypercoagulable states, as well as the postopera-tive state. Venous pathology is often, but not always, associated with visible or palpable signs that can be identified during the physical examination. There is variation among individuals in the prominence of superficial veins when the person is standing (Fig. 24-1). The superficial veins of a lean athletic person, even when normal, will appear large and easily visualized, but these veins will be far less obvious in the obese individual. Signs of superficial venous abnormalities are listed in Table 24-1. Key Points1 Thrombolytic therapy, surgical thrombectomy, and place-ment of inferior vena cava filters are adjunctive treatments that may be indicated in patients with extensive and compli-cated venous thromboembolism.2 Deep vein thrombosis (DVT) and pulmonary embolism are well-recognized complications after major abdominal and orthopedic procedures. The risk is further increased in patients with


Surgery_Schwartz

Surgery_Schwartz. thromboembolism.2 Deep vein thrombosis (DVT) and pulmonary embolism are well-recognized complications after major abdominal and orthopedic procedures. The risk is further increased in patients with malignancy and a history of venous thrombo-embolism. Options for DVT prophylaxis include intermit-tent pneumatic compression, use of graduated compression stockings, and administration of low-dose unfractionated heparin, low molecular weight heparin, fondaparinux, and vitamin K antagonists. Direct thrombin inhibitors and factor Xa inhibitors are approved for prophylactic use only for orthopedic procedures and for recurrent VTE. However, prophylaxis should be stratified based on the patient’s level of risk.3 In patients with established DVT, unfractionated heparin, low molecular weight heparin, fondaparinux, and some factor Xa inhibitors are options for initial antithrombotic therapy. Vitamin-K antagonists, direct thrombin inhibitors, and factor Xa inhibitors are utilized for long-term


Surgery_Schwartz

Surgery_Schwartz. fondaparinux, and some factor Xa inhibitors are options for initial antithrombotic therapy. Vitamin-K antagonists, direct thrombin inhibitors, and factor Xa inhibitors are utilized for long-term anticoagulation. The duration and type of long-term anticoagulation should be stratified based on the provoked or unprovoked nature of the DVT, the location of the DVT, previous occurrence of DVT, and presence of concomitant malignancy.4 High ligation and stripping, endovenous laser, or radiofre-quency ablation and sclerotherapy are effective therapies for patients with saphenous vein valvular insufficiency. Con-comitant varicose veins may be managed with compression therapy, sclerotherapy, and phlebectomy. New nonthermal ablative techniques, including the combination of sclero-therapy with endoluminal mechanical injury as well as injec-tion of cyanoacrylate, show early promising results.5 The mainstay of treatment for chronic venous insufficiency is compression therapy. Sclerotherapy,


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Surgery_Schwartz. endoluminal mechanical injury as well as injec-tion of cyanoacrylate, show early promising results.5 The mainstay of treatment for chronic venous insufficiency is compression therapy. Sclerotherapy, perforator vein liga-tion, and venous reconstruction or ablative techniques may be indicated in patients in whom conservative management fails or as a means to decrease ulcer recurrence.6 Lymphedema is categorized as congenital, primary (with early or delayed onset), or secondary. The goals of treatment are to minimize edema and prevent infection. Lymphatic massage, sequential pneumatic compression, use of com-pression garments, and limb elevation are effective forms of therapy.Brunicardi_Ch24_p0981-p1008.indd 98222/02/19 3:00 PM 983VENOUS AND LYMPHATIC DISEASECHAPTER 24Figure 24-1. Varicose vein demonstrating evidence of chronic venous insufficiency.Figure 24-2. Characteristic hyperpigmentation of chronic venous insufficiency.Table 24-1Possible signs of superficial venous


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Surgery_Schwartz. 24-1. Varicose vein demonstrating evidence of chronic venous insufficiency.Figure 24-2. Characteristic hyperpigmentation of chronic venous insufficiency.Table 24-1Possible signs of superficial venous abnormalitiesTortuosityVaricosityVenous sacculeDistended subdermal venules (corona phlebectatica)Distended intradermal venules (spider angiomata)Warmth, erythema, tenderness (superficial thrombophlebitis)The deep veins cannot be directly assessed clinically, and abnormalities within them can only be inferred indirectly from changes found on clinical examination.Chronic venous insufficiency (CVI) may lead to character-istic changes in the skin and subcutaneous tissues in the affected limb. CVI results from incompetence of venous valves, venous obstruction, or both. Most CVI involves venous reflux, and severe CVI often reflects a combination of reflux and venous obstruction. It is important to remember that although CVI originates with abnormalities of the veins, the target organ of CVI is


Surgery_Schwartz

Surgery_Schwartz. and severe CVI often reflects a combination of reflux and venous obstruction. It is important to remember that although CVI originates with abnormalities of the veins, the target organ of CVI is the skin, and the underlying physiologic and biochemical mechanisms leading to the cutaneous abnormalities associated with CVI are poorly understood. A typical leg affected by CVI will be edematous, with edema increasing over the course of the day. The leg may also be indurated and pigmented with eczema and dermatitis. These changes are associated with excessive proteinaceous capillary exudate. Deposition of a pericapil-lary fibrin cuff may limit nutritional exchange. In addition, an increase in white blood cell trapping within the skin microcir-culation in CVI patients may lead to microvascular congestion and thrombosis. Subsequently, white blood cells may migrate into the interstitium and release necrotizing lysosomal enzymes, potentially leading to tissue destruction and eventual


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Surgery_Schwartz. congestion and thrombosis. Subsequently, white blood cells may migrate into the interstitium and release necrotizing lysosomal enzymes, potentially leading to tissue destruction and eventual ulceration.Fibrosis can eventually develop from impaired nutrition, chronic inflammation, and fat necrosis (lipodermatosclerosis). Hemosiderin deposition due to the extravasation of red cells and subsequent lysis in the skin contributes to the characteristic pigmentation of chronic venous disease (Fig. 24-2). Ulceration can develop with longstanding venous hypertension and is associated with alterations in microcirculatory and cutaneous lymphatic anatomy and function. The most common location of venous ulceration is approximately 3 cm proximal to the medial malleolus, frequently referred to the “gaiter” region (Fig. 24-3).Trendelenburg’s test is a clinical test, historically impor-tant but now rarely used, that can help determine whether incompetent valves are present and in which of the three


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Surgery_Schwartz. region (Fig. 24-3).Trendelenburg’s test is a clinical test, historically impor-tant but now rarely used, that can help determine whether incompetent valves are present and in which of the three venous systems (superficial, deep, or perforator) the valves are abnormal. There are two components to this test. First, with the patient supine, the leg is elevated 45° to empty the veins, and the GSV is occluded with the examiner’s hand or with a rub-ber tourniquet. Then, with the GSV still occluded, the patient stands, and the superficial veins are observed for blood filling. The compression on the GSV is released, and the superficial veins are observed for filling with blood. A positive result is the sudden filling of veins with standing while the GSV remains occluded, indicating incompetent perforator and deep veins. Additionally, the GSV valves are incompetent if rapid filling is noted following release of compression. A negative result, indicating no clinically relevant venous reflux, is


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Surgery_Schwartz. and deep veins. Additionally, the GSV valves are incompetent if rapid filling is noted following release of compression. A negative result, indicating no clinically relevant venous reflux, is the gradual filling of the veins from arterial inflow. Interpretation of the findings of Trendelenburg’s test is subjective, and therefore, it has largely been supplanted by the more objective noninvasive vascular laboratory tests to localize sites of venous reflux.Noninvasive Evaluation. Before the development of vascu-lar ultrasound, noninvasive techniques to evaluate the venous system were based on plethysmographic techniques. Although a variety of plethysmographic techniques are used in the Brunicardi_Ch24_p0981-p1008.indd 98322/02/19 3:01 PM 984SPECIFIC CONSIDERATIONSPART IIFigure 24-3. Venous ulceration located proximal to the medial malleolus.evaluation of both acute and chronic venous disease, they are all based on the detection of volume changes in the limb in response to blood


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Surgery_Schwartz. ulceration located proximal to the medial malleolus.evaluation of both acute and chronic venous disease, they are all based on the detection of volume changes in the limb in response to blood flow.Duplex ultrasonography (DUS) augmented by color flow imaging is now the most important noninvasive diagnos-tic method in the evaluation of the venous system. DUS has become standard for the detection of infrainguinal deep vein thrombosis (DVT), with near 100% sensitivity and specificity in symptomatic patients.3 It is also the preferred method of evalu-ation for upper extremity venous thrombosis and is useful in the evaluation of CVI by documenting the presence of valvular reflux and venous obstruction. Overlying bowel gas and large body habitus many times make DUS less applicable to evalu-ation of intra-abdominal veins. Magnetic resonance venogra-phy (MRV) and computed tomography (CT) venography are alternative noninvasive techniques for evaluation of pelvic and intra-abdominal


Surgery_Schwartz

Surgery_Schwartz. evalu-ation of intra-abdominal veins. Magnetic resonance venogra-phy (MRV) and computed tomography (CT) venography are alternative noninvasive techniques for evaluation of pelvic and intra-abdominal veins.Invasive Evaluation. Improved accuracy of noninvasive techniques for diagnostic purposes has made the use of invasive procedures more selective. Both venography and intravascular ultrasound (IVUS) are used as adjuncts to percutaneous or open surgical treatment of venous disorders. When planning endo-vascular or open surgical treatment, venography may be used to identify areas of obstruction in infrainguinal, intra-abdominal, and upper extremity veins as well as reflux in intra-abdominal and infrainguinal veins. IVUS, with access generally via the common femoral vein, is used primarily to assess for occlusive lesions of the iliac veins and appears more sensitive than venog-raphy in detecting iliac vein obstruction.4Complications of venography include pain, thrombosis, or hematoma at


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Surgery_Schwartz. assess for occlusive lesions of the iliac veins and appears more sensitive than venog-raphy in detecting iliac vein obstruction.4Complications of venography include pain, thrombosis, or hematoma at the puncture site. Pain is lower with nonionic low-osmolality contrast media than with conventional contrast agents (with 18% vs. 44% of patients experiencing discomfort, respectively).5 Systemic effects of iodinated contrast media include allergic reaction and risk of renal failure. Postvenogra-phy venous thrombosis occurs distal to the venous puncture site in 1% to 9% of patients undergoing venography secondary to intimal damage from the intravenous (IV) contrast agent.5 Com-plications and limitations of IVUS are related to complications at the access site and cost of the catheters.VENOUS THROMBOEMBOLISMEpidemiologyDespite increased awareness and use of prophylactic modalities, DVT or pulmonary embolism (PE), venous thromboembolism (VTE), remain important preventable sources of morbidity


Surgery_Schwartz

Surgery_Schwartz. increased awareness and use of prophylactic modalities, DVT or pulmonary embolism (PE), venous thromboembolism (VTE), remain important preventable sources of morbidity and mortality, especially in the surgical patient. The incidence of VTE is approximately 100 per 100,000 people per year in the general population, with 20% of the diagnoses made within 3 months of a surgical procedure. Of the symptomatic patients, one-third will present with PE and two-thirds with DVT.6,7 The estimated number of cases of VTE may well be over 600,000 per year in the United States, making it a major U.S. health problem.8 Furthermore, death occurs in 6% of DVT and 12% of PE cases within 1 month of diagnosis, although not all deaths are directly secondary to VTE, with many related to the under-lying problem leading to the VTE event.6 However, not only does VTE pose a veritable threat to life, it also places patients at higher risk for recurrence and post-VTE sequelae such as pul-monary hypertension and


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Surgery_Schwartz. leading to the VTE event.6 However, not only does VTE pose a veritable threat to life, it also places patients at higher risk for recurrence and post-VTE sequelae such as pul-monary hypertension and postthrombotic syndrome, with 4% and up to 30% incidence, respectively.9-11Risk FactorsThree broadly stated conditions, first described by Rudolf Vir-chow in 1862, contribute to VTE formation: stasis of blood flow, endothelial damage, and hypercoagulability. Of these risk factors, relative hypercoagulability appears most impor-tant in cases of spontaneous VTE, or so-called idiopathic VTE, whereas stasis and endothelial damage likely play a greater role in secondary VTE, or so-called provoked VTE, occurring in association with transient risk factors such as immobiliza-tion, surgical procedures, and trauma. Identifiable risk factors for VTE generally relate to one of the conditions described by Virchow. Often more than one risk factor is present contribut-ing in an exponential, rather than


Surgery_Schwartz

Surgery_Schwartz. and trauma. Identifiable risk factors for VTE generally relate to one of the conditions described by Virchow. Often more than one risk factor is present contribut-ing in an exponential, rather than additive, manner. Specific risk factors for VTE are listed in Table 24-2.The more common acquired VTE risk factors include older age (>40 years), hospitalization and immobilization, hor-mone replacement and oral contraceptive therapy, pregnancy and the recently postpartum state, prior VTE, malignancy, major surgery, obesity, nephrotic syndrome, trauma and spinal cord injury, long-haul travel (>6 hours), varicose veins, antiphospho-lipid syndrome, myeloproliferative disorders, and polycythemia. Heritable risk factors include male sex, factor V Leiden muta-tion; prothrombin 20210A gene variant; antithrombin, protein C, and protein S deficiencies; and dysfibrinogenemias. In some patients, the cause of the thrombophilia may have both a heri-table and an acquired component. These mixed causes


Surgery_Schwartz

Surgery_Schwartz. antithrombin, protein C, and protein S deficiencies; and dysfibrinogenemias. In some patients, the cause of the thrombophilia may have both a heri-table and an acquired component. These mixed causes include homocysteinemia; factors VII, VIII, IX, and XI elevation; hyperfibrinogenemia; and activated protein C resistance in the Brunicardi_Ch24_p0981-p1008.indd 98422/02/19 3:01 PM 985VENOUS AND LYMPHATIC DISEASECHAPTER 24Table 24-2Risk factors for venous thromboembolismAcquiredAdvanced ageHospitalization/immobilizationHormone replacement therapy and oral contraceptive usePregnancy and puerperiumPrior venous thromboembolismMalignancyMajor surgeryObesityNephrotic syndromeTrauma or spinal cord injuryLong-haul travel (>6 hours)Varicose veinsAntiphospholipid antibody syndromeMyeloproliferative diseasePolycythemiaInheritedFactor V LeidenProthrombin 20210AAntithrombin deficiencyProtein C deficiencyProtein S deficiencyFactor XI elevationDysfibrinogenemiaMixed EtiologyHomocysteinemiaFactors


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Surgery_Schwartz. diseasePolycythemiaInheritedFactor V LeidenProthrombin 20210AAntithrombin deficiencyProtein C deficiencyProtein S deficiencyFactor XI elevationDysfibrinogenemiaMixed EtiologyHomocysteinemiaFactors VII, VIII, IX, XI elevationHyperfibrinogenemiaActivated protein C resistance without factor V Leidenabsence of factor V Leiden.12 There may be a synergistic effect when particular multiple inherited and acquired risk factors are present in the same patient.Other patient-specific factors associated with venous thrombosis include the traditional cardiovascular risk factors of obesity, hypertension, and diabetes. VTE is more common in whites and African Americans than Asians and Native Americans.13,14 Certain gene variants (single nucleotide polymorphisms) are also associated with a mildly increased risk for VTE, and their presence may interact with other risk factors to increase the overall risk for venous thrombosis.15Anatomic factors may also contribute to development of DVT. At the site


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Surgery_Schwartz. risk for VTE, and their presence may interact with other risk factors to increase the overall risk for venous thrombosis.15Anatomic factors may also contribute to development of DVT. At the site where the right iliac artery crosses over the left iliac vein, the left iliac vein may become chronically compressed predisposing to iliofemoral venous thrombosis, so-called May-Thurner syndrome. External compression of major veins by masses of various types can also lead to venous thrombosis.Many cases of VTE are potentially preventable. Accord-ingly, in current clinical practice, preoperative VTE risk assess-ment is becoming increasingly common to identify patients at moderate and high risk. Scoring systems have been developed that take into account the number of VTE risk factors in an individual patient. These risk stratification scores, such as the Rogers score16 and Caprini score,17 provide individual patient risk stratification and recommendations for prophylactic anti-coagulation. The


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Surgery_Schwartz. patient. These risk stratification scores, such as the Rogers score16 and Caprini score,17 provide individual patient risk stratification and recommendations for prophylactic anti-coagulation. The ninth edition of the American College of Chest Physicians (ACCP) Guidelines for Prevention of VTE in Non-Orthopedic Surgical Patients acknowledges both the Rogers and Caprini scores and provides recommendations for VTE prophylaxis (Table 24-3). Orthopedic surgical patients are generally excluded from risk assessment scores because of the disproportionately increased risk of VTE in orthopedic surgery compared with the general and abdominopelvic surgery population.Table 24-3Thromboembolism risk and recommended thromboprophylaxis in surgical patientsLEVEL OF RISKAPPROXIMATE DVT RISK WITHOUT THROMBOPROPHYLAXIS (%)SUGGESTED THROMBOPROPHYLAXIS OPTIONSVery low risk General or abdominopelvic surgery<0.5% (Rogers score <7; Caprini score 0)No specific thromboprophylaxisEarly ambulationLow


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Surgery_Schwartz. THROMBOPROPHYLAXIS (%)SUGGESTED THROMBOPROPHYLAXIS OPTIONSVery low risk General or abdominopelvic surgery<0.5% (Rogers score <7; Caprini score 0)No specific thromboprophylaxisEarly ambulationLow risk General or abdominopelvic surgery∼1.5% (Rogers score 7–10; Caprini score 1–2)Mechanical prophylaxisModerate risk General or abdominopelvic surgery∼3.0% (Rogers score >10; Caprini score 3–4)LMWH (at recommended doses), LDUH, or mechanical prophylaxisHigh bleeding risk Mechanical prophylaxisHigh risk General or abdominopelvic surgery∼6% (Caprini score ≥5)LMWH (at recommended doses), fondaparinux and mechanical prophylaxisHigh bleeding risk General or abdominopelvic surgery for cancer Mechanical thromboprophylaxisExtended-duration LMWH (4 weeks)DVT = deep vein thrombosis; INR = international normalized ratio; LDUH = low-dose unfractionated heparin; LMWH = low molecular weight heparin; VTE = venous thromboembolism.Data from Gould MK, Garcia DA, Wren SM, et al: Prevention of VTE in


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Surgery_Schwartz. normalized ratio; LDUH = low-dose unfractionated heparin; LMWH = low molecular weight heparin; VTE = venous thromboembolism.Data from Gould MK, Garcia DA, Wren SM, et al: Prevention of VTE in nonorthopedic surgical patients: Antithrombotic Therapy and Prevention of Thrombosis, 9th ed: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines, Chest. 2012 Feb;141(2 Suppl):e227S-e277S.Brunicardi_Ch24_p0981-p1008.indd 98522/02/19 3:01 PM 986SPECIFIC CONSIDERATIONSPART IIFigure 24-4. Phlegmasia cerulea dolens of the left leg. Note the bluish discoloration.Figure 24-5. Duplex ultrasound scan of a normal femoral vein with phasic flow signals.DiagnosisClinical Evaluation. Early in the course of DVT development, venous thrombosis is thought to begin in an area of relative stasis, such as a soleal sinus vein or immediately downstream of the cusps of a venous valve in an axial calf vein. Isolated proxi-mal DVT without tibial vein thrombosis is unusual. Early in the


Surgery_Schwartz

Surgery_Schwartz. stasis, such as a soleal sinus vein or immediately downstream of the cusps of a venous valve in an axial calf vein. Isolated proxi-mal DVT without tibial vein thrombosis is unusual. Early in the course of a DVT, there may be no or few clinical findings such as pain or swelling. Even extensive DVT may sometimes be present without signs or symptoms if the patient is nonambula-tory or bedbound. History and physical examination are notori-ously unreliable in the diagnosis of DVT. In addition, symptoms and signs often associated with DVT, such as extremity pain and/or swelling, are nonspecific. In large studies, DVT has been found by venography or DUS in ≤50% of patients in whom it was clinically suspected.18,19 Objective studies are therefore required to confirm a diagnosis of VTE or to exclude the pres-ence of VTE.Clinical symptoms may worsen as DVT propagates and involves the major proximal deep veins. Extensive DVT of the major axial deep venous channels of the lower extremity with


Surgery_Schwartz

Surgery_Schwartz. the pres-ence of VTE.Clinical symptoms may worsen as DVT propagates and involves the major proximal deep veins. Extensive DVT of the major axial deep venous channels of the lower extremity with rel-ative sparing of collateral veins causes a condition called phleg-masia cerulea dolens (Fig. 24-4). This condition is characterized by pain and pitting edema with associated cyanosis. When the thrombosis extends to the collateral veins, massive fluid seques-tration and more significant edema ensue, resulting in a condition known as phlegmasia alba dolens.20 The affected extremity in phlegmasia alba dolens is extremely painful and edematous and pale secondary to arterial insufficiency from dramatically ele-vated below lower knee compartment pressures. Both phlegmasia cerulean dolens and phlegmasia alba dolens can be complicated by venous gangrene and the need for amputation.Vascular Lab and Radiologic Evaluation Duplex Ultrasound DUS is now the most commonly per-formed test for the detection


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Surgery_Schwartz. alba dolens can be complicated by venous gangrene and the need for amputation.Vascular Lab and Radiologic Evaluation Duplex Ultrasound DUS is now the most commonly per-formed test for the detection of infrainguinal DVT, both above and below the knee, and has a sensitivity and specificity of >95% in symptomatic patients.3 DUS refers to the combina-tion of real-time B-mode ultrasound with compression and flow augmentation amneuvres combined with pulsed Doppler capa-bility. For VTE detection, color flow imaging is an additional extremely useful adjunct in the evaluation of possible axial calf vein DVT and evaluation of intra-abdominal veins. DUS provides the ability to noninvasively visualize venous anatomy, detect occluded and partially occluded venous segments, and demonstrate physiologic flow characteristics.In the supine patient, normal lower extremity venous flow is phasic (Fig. 24-5), decreasing with inspiration in response to increased intra-abdominal pressure with the descent of


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Surgery_Schwartz. flow characteristics.In the supine patient, normal lower extremity venous flow is phasic (Fig. 24-5), decreasing with inspiration in response to increased intra-abdominal pressure with the descent of the diaphragm and then increasing with expiration as the diaphragm rises and intra-abdominal pressure decreases. When the patient is upright, the decrease in intra-abdominal pressure with expira-tion cannot overcome the hydrostatic column of pressure exist-ing between the right atrium and the calf. Muscular contractions of the calf, along with the one-way venous valves, are then required to promote venous return to the heart. Flow also can be increased by leg elevation or compression and decreased by sud-den elevation of intra-abdominal pressure (Valsalva maneuver). In a venous DUS examination performed with the patient supine, spontaneous flow, variation of flow with respiration, and response of flow to Valsalva maneuver are all assessed. From the common femoral through the popliteal


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Surgery_Schwartz. performed with the patient supine, spontaneous flow, variation of flow with respiration, and response of flow to Valsalva maneuver are all assessed. From the common femoral through the popliteal vein, the primary method of detecting DVT with ultrasound is demonstration of the lack of compressibility of the vein with probe pressure on B-mode imaging. Normally, in transverse section, the vein walls should coapt with pressure. Lack of coaptation indicates throm-bus. Axial calf vein thrombi are often best detected by abnor-malities in color flow imaging as compressibility is difficult in the calf.The examination begins at the ankle and continues proxi-mally to the groin. Each vein is visualized, and the flow signal is assessed with distal and proximal compression. Lower extremity DVT can be diagnosed by any of the following DUS findings: lack of spontaneous flow (Fig. 24-6), inability to compress the vein (Fig. 24-7), absence of color filling of the lumen by color flow DUS, loss of


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Surgery_Schwartz. be diagnosed by any of the following DUS findings: lack of spontaneous flow (Fig. 24-6), inability to compress the vein (Fig. 24-7), absence of color filling of the lumen by color flow DUS, loss of respiratory flow variation, and venous disten-tion. Again, lack of venous compression on B-mode imaging is the primary diagnostic variable. Several studies comparing B-mode ultrasound to venography for the detection of femo-ropopliteal DVT in patients clinically suspected to have DVT report sensitivities of >91% and specificities of >97%.21,22 The ability of DUS to assess isolated calf vein DVT varies greatly, with sensitivities ranging from 50% to 93% and specificities approaching 100%.23,24Impedance Plethysmography Impedance plethysmography (IPG) was the primary noninvasive method of diagnosing DVT before the widespread use of DUS but is infrequently used today. Changes in electrical resistance resulting from lower extremity blood volume changes are quantified. IPG is less accurate than


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Surgery_Schwartz. DVT before the widespread use of DUS but is infrequently used today. Changes in electrical resistance resulting from lower extremity blood volume changes are quantified. IPG is less accurate than DUS for the detection of proximal DVT, with 83% sensitivity in symptomatic patients. It is a poor detector of calf vein DVT.25Brunicardi_Ch24_p0981-p1008.indd 98622/02/19 3:01 PM 987VENOUS AND LYMPHATIC DISEASECHAPTER 24Figure 24-6. Duplex ultrasound of a femoral vein containing thrombus demonstrating no flow within the femoral vein.No compressionCompressionR FVPR FVPFigure 24-7. B-mode ultrasound of the femoral vein in crosssection. The femoral vein does not collapse with external compres-sion (arrows).Figure 24-8. Venogram showing a filling defect in the popliteal vein (arrows).Iodine-125 Fibrinogen Uptake Iodine-125 fibrinogen uptake (FUT) is a seldom-used technique that involves IV administra-tion of radioactive fibrinogen and monitoring for increased uptake in fibrin clots. An


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Surgery_Schwartz. Fibrinogen Uptake Iodine-125 fibrinogen uptake (FUT) is a seldom-used technique that involves IV administra-tion of radioactive fibrinogen and monitoring for increased uptake in fibrin clots. An increase of 20% or more in one area of a limb indicates an area of thrombus. FUT can detect DVT in the calf, but high background radiation from the pelvis and the urinary tract limits its ability to detect proximal DVT. It also cannot be used in an extremity that has recently undergone surgery or has active inflammation. In a prospective study, FUT had a sensitivity of 73% and specificity of 71% for identification of DVT in a group of symptomatic and asymptomatic patients.26 Currently, FUT is primarily a research tool of historic interest.Venography Venography is the gold standard to which other diagnostic modalities are compared. A small catheter is placed in a dorsal foot vein with injection of a radiopaque contrast agent. Radiographs are obtained in at least two projections. A positive


Surgery_Schwartz

Surgery_Schwartz. diagnostic modalities are compared. A small catheter is placed in a dorsal foot vein with injection of a radiopaque contrast agent. Radiographs are obtained in at least two projections. A positive study result is failure to fill the deep system with passage of the contrast medium into the superficial system or demonstration of discrete filling defects (Fig. 24-8). A normal study result virtually excludes the presence of DVT. In a study of 160 patients with a normal venogram followed for 3 months, only two patients (1.3%) subsequently developed DVT, and no patients experienced symptoms of PE.27 Venography is not routinely used in clinical practice because of its invasiveness and complication risk. It is still, however, sometimes used in research studies evaluating DVT prophylaxis.TreatmentOnce the diagnosis of VTE has been made, antithrombotic ther-apy should be initiated promptly. If clinical suspicion for VTE is high, it may be prudent to start treatment before the diagnosis is


Surgery_Schwartz

Surgery_Schwartz. the diagnosis of VTE has been made, antithrombotic ther-apy should be initiated promptly. If clinical suspicion for VTE is high, it may be prudent to start treatment before the diagnosis is objectively confirmed. The goals of VTE treatment are the pre-vention of mortality and morbidity associated with PE and the prevention of the postthrombotic syndrome (PTS). Treatment regimens may include antithrombotic therapy, temporary or permanent vena cava filter placement, catheter-directed or systemic thrombolytic therapy, and operative thrombectomy.Antithrombotic Therapy. Most often, antithrombotic therapy for VTE is initiated with IV or subcutaneous (SC) unfraction-ated heparin or SC low molecular weight heparin. Fondaparinux, a synthetic pentasaccharide, is sometimes also used as an alter-native to heparin to initiate therapy. An oral vitamin K antago-nist, usually sodium warfarin, is begun shortly after initiation of IV or SC therapy. Either SC or IV therapy is continued until effective


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Surgery_Schwartz. to heparin to initiate therapy. An oral vitamin K antago-nist, usually sodium warfarin, is begun shortly after initiation of IV or SC therapy. Either SC or IV therapy is continued until effective oral anticoagulation with warfarin is achieved as indi-cated by an international normalized ratio (INR) ≥2 for 24 hours. A minimum of 5 days of heparin or fondaparinux therapy is 1Brunicardi_Ch24_p0981-p1008.indd 98722/02/19 3:01 PM 988SPECIFIC CONSIDERATIONSPART IIrecommended.28 Recently, several oral anticoagulants that function by either directly inhibiting thrombin or inhibit-ing factor Xa have additionally been approved by the United States Food and Drug Administration (FDA) for both treatment and prophylaxis for VTE. A principle advantage is they do not require monitoring of laboratory parameters for use.Unfractionated heparin (UFH) binds to antithrombin via a specific 18-saccharide sequence. This increases antithrombin activity over a thousandfold. The antithrombin-heparin complex


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Surgery_Schwartz. parameters for use.Unfractionated heparin (UFH) binds to antithrombin via a specific 18-saccharide sequence. This increases antithrombin activity over a thousandfold. The antithrombin-heparin complex primarily inhibits factor IIa (thrombin) and factor Xa and, to a lesser degree, factors IXa, XIa, and XIIa of the coagulation cascade. In addition, UFH also binds to tissue factor pathway inhibitor, which inhibits the conversion of factors X to Xa, and factors IX to IXa. Finally, UFH catalyzes the inhibition of thrombin by heparin cofactor II via a mechanism independent of antithrombin.UFH therapy is most commonly administered with an initial IV bolus of 80 units/kg. Weight-based UFH dosages have been shown to be more effective than standard fixed boluses in rapidly achieving therapeutic levels.29 The initial bolus is followed by a continuous IV drip at 18 units/kg per hour. The half-life of IV UFH ranges from 45 to 90 minutes and is dose dependent. The level of antithrombotic therapy


Surgery_Schwartz

Surgery_Schwartz. The initial bolus is followed by a continuous IV drip at 18 units/kg per hour. The half-life of IV UFH ranges from 45 to 90 minutes and is dose dependent. The level of antithrombotic therapy should be moni-tored every 6 hours using the activated partial thromboplastin time (aPTT), with the goal range of 1.5 to 2.5 times control values. This should correspond with plasma heparin anti-Xa activity levels of 0.3 to 0.7 IU/mL.Initial anticoagulation with UFH may also be administered SC, although this route is less commonly used. Adjusted-dose therapeutic SC UFH is initiated with 17,500 units, followed by 250 units/kg twice daily, and dosing is adjusted to an aPTT goal range similar to that for IV UFH. Fixed-dose unmonitored SC UFH is started with a bolus of 333 units/kg, followed by 250 units/kg twice daily.30Hemorrhage is the primary complication of UFH therapy. The rate of major hemorrhage (fatal, intracranial, retroperitoneal, or requiring transfusion of >2 units of packed red blood


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Surgery_Schwartz. twice daily.30Hemorrhage is the primary complication of UFH therapy. The rate of major hemorrhage (fatal, intracranial, retroperitoneal, or requiring transfusion of >2 units of packed red blood cells) is approximately 5% in hospitalized patients undergoing UFH therapy (1% in medical patients and 8% in surgical patients).30 For patients with UFH-related bleeding complications, cessation of UFH is required, and anticoagulation may be reversed with protamine sulfate. Protamine sulfate binds to UFH and forms an inactive salt compound. Each milligram of protamine neutral-izes 90 to 115 units of heparin, and the dosage should not exceed 50 mg IV over any 10-minute period. Side effects of protamine sulfate include hypotension, pulmonary edema, and anaphylaxis. Patients with prior exposure to protamine-containing insulin (NPH) and patients with allergy to fish may have an increased risk of hypersensitivity, although no direct relationship has been established. Protamine administration should


Surgery_Schwartz

Surgery_Schwartz. insulin (NPH) and patients with allergy to fish may have an increased risk of hypersensitivity, although no direct relationship has been established. Protamine administration should be performed judi-ciously and terminated if any side effects occur.In addition to hemorrhage, heparin also has other, unique, complications. Heparin-induced thrombocytopenia (HIT) results from heparin-associated antiplatelet antibodies (HAAbs) directed against platelet factor 4 complexed with heparin.31 HIT occurs in 1% to 5% of patients treated with heparin.32,33 In patients with repeat heparin exposure (such as vascular surgery patients), the incidence of HAAbs may be as high as 21%.34 HIT occurs most frequently in the second week of therapy and may lead to disastrous venous or arterial thrombotic complications. Therefore, platelet counts should be monitored periodically in patients receiving continuous heparin therapy.HIT is diagnosed based on previous exposure to heparin, platelet count less than


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Surgery_Schwartz. Therefore, platelet counts should be monitored periodically in patients receiving continuous heparin therapy.HIT is diagnosed based on previous exposure to heparin, platelet count less than 100,000, and/or platelet count decline of 50% following exposure. All heparin must be stopped and alter-native anticoagulation initiated immediately to avoid thrombotic complications, which may approach 50% over the subsequent 30 days in affected individuals.35Another complication of prolonged high-dose heparin therapy is osteopenia. Heparin-induced osteopenia results from impairment of bone formation and enhancement of bone resorp-tion by heparin.Low molecular weight heparins (LMWHs) are derived from the depolymerization of porcine UFH. Like UFH, LMWHs bind to antithrombin via a specific pentasaccharide sequence to expose an active site for the neutralization of fac-tor Xa. However, LMWHs have fewer additional saccharide units. This results in less inactivation of thrombin (factor IIa). In


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Surgery_Schwartz. sequence to expose an active site for the neutralization of fac-tor Xa. However, LMWHs have fewer additional saccharide units. This results in less inactivation of thrombin (factor IIa). In comparison to UFH, LMWHs have increased bioavailability (>90% after SC injection), longer half-lives (approximately 4 to 6 hours), and more predictable elimination rates.Most patients treated with weight-based onceor twice-daily SC LMWH injections do not require laboratory monitoring for anticoagulant effect, a distinct advantage over continuous IV infusions of UFH. Patients who do require monitoring include those with significant renal insufficiency, pediatric patients, obese patients greater than 120 kg, and pregnant patients. Moni-toring may be performed using anti-Xa activity assays. The ther-apeutic anti-Xa goal range depends on the type of LMWH and the frequency of dosing. There are numerous LMWHs avail-able, and the various preparations differ in their anti-Xa and anti-IIa activities.


Surgery_Schwartz

Surgery_Schwartz. anti-Xa goal range depends on the type of LMWH and the frequency of dosing. There are numerous LMWHs avail-able, and the various preparations differ in their anti-Xa and anti-IIa activities. Treatment dosing for one LMWH, therefore, cannot be extrapolated for use with another. The anticoagulant effect of LMWHs may be partially reversed (approximately 60%) with protamine sulfate.Numerous well-designed trials comparing SC LMWH with IV and SC UFH for the treatment of DVT have been critically evaluated in several meta-analyses and demonstrate a decrease in thrombotic complications, bleeding, and mortality with LMWHs.36-38 LMWHs also are associated with a decreased rate of HAAb formation and HIT (<2%) compared with UFH (at least in prophylactic doses).30 However, patients with estab-lished HIT also should not receive LMWHs because there is cross-reactivity between the drugs.39A major benefit of LMWHs is that it allows outpatient treatment of VTE.40,41 In a randomized study comparing IV UFH


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Surgery_Schwartz. also should not receive LMWHs because there is cross-reactivity between the drugs.39A major benefit of LMWHs is that it allows outpatient treatment of VTE.40,41 In a randomized study comparing IV UFH and the LMWH nadroparin calcium,40 there was no sig-nificant difference in recurrent thromboembolism (8.6% for UFH vs. 6.9% for LMWH) or major bleeding complications (2.0% for UFH vs. 0.5% for LMWH). There was, however, a 67% reduction in mean days in the hospital for the LMWH group.Fondaparinux currently is a synthetic pentasaccharide that has been approved by the FDA for the initial treatment of DVT and PE. Its five-polysaccharide sequence binds and activates antithrombin, causing specific inhibition of factor Xa. In two large noninferiority trials, fondaparinux was compared with the LMWH enoxaparin for the initial treatment of DVT and with IV UFH for the initial treatment of PE.42,43 The rates of recurrent VTE ranged from 3.8% to 5%, with rates of major bleeding of 2% to 2.6%, for all


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Surgery_Schwartz. for the initial treatment of DVT and with IV UFH for the initial treatment of PE.42,43 The rates of recurrent VTE ranged from 3.8% to 5%, with rates of major bleeding of 2% to 2.6%, for all treatment arms. The drug is administered SC once daily with a weight-based dosing protocol: 5 mg, 7.5 mg, or 10 mg for patients weighing <50 kg, 50 to 100 kg, or >100 kg, respectively. The half-life of fondaparinux is approximately 2Brunicardi_Ch24_p0981-p1008.indd 98822/02/19 3:01 PM 989VENOUS AND LYMPHATIC DISEASECHAPTER 2417 hours in patients with normal renal function. There are rare case reports of fondaparinux-induced thrombocytopenia.44Direct thrombin inhibitors (DTIs) include parental forms with recombinant hirudin, argatroban, and bivalirudin, as well as an oral agent, dabigatran. These antithrombotic agents bind to thrombin, inhibiting the conversion of fibrinogen to fibrin as well as thrombin-induced platelet activation. These actions are independent of antithrombin. The parental


Surgery_Schwartz

Surgery_Schwartz. antithrombotic agents bind to thrombin, inhibiting the conversion of fibrinogen to fibrin as well as thrombin-induced platelet activation. These actions are independent of antithrombin. The parental DTIs should be reserved for (a) patients in whom there is a high clinical suspi-cion or confirmation of HIT, and (b) patients who have a his-tory of HIT or test positive for heparin-associated antibodies whereas dabigatran can be used as an alternative to Warfarin when INR monitoring is difficult or impractical. In patients with established HIT, DTIs should be administered for at least 7 days, or until the platelet count normalizes. Warfarin may then be introduced slowly, overlapping therapy with a DTI for at least 5 days, or dabigatran may be continued instead of Warfarin.45Bivalirudin is approved primarily for patients with or without HIT who undergo percutaneous coronary intervention and is rarely used outside of that setting.Argatroban is indicated for the prophylaxis and treatment of


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Surgery_Schwartz. primarily for patients with or without HIT who undergo percutaneous coronary intervention and is rarely used outside of that setting.Argatroban is indicated for the prophylaxis and treatment of thrombosis in HIT. It also is approved for patients with, or at risk for, HIT undergoing percutaneous coronary intervention. Antithrombotic prophylaxis and therapy are initiated with a con-tinuous IV infusion of 2 µg/kg per minute, without the need for a bolus. The half-life ranges from 39 to 51 minutes, and the dosage is adjusted to maintain an aPTT of 1.5 to 3 times normal. Large ini-tial boluses and higher rates of continuous infusion are reserved for patients with coronary artery thrombosis and myocardial infarc-tion. In these patients, therapy is monitored using the activated clotting time. Argatroban is metabolized and excreted by the liver; therefore, dosage adjustments are needed in patients with hepatic impairment. There is no reversal agent for argatroban.The oral agent, dabigatran,


Surgery_Schwartz

Surgery_Schwartz. is metabolized and excreted by the liver; therefore, dosage adjustments are needed in patients with hepatic impairment. There is no reversal agent for argatroban.The oral agent, dabigatran, is US FDA-approved since 2014 for the treatment of VTE and prophylaxis for recurrent VTE. Additionally, limited approval was obtained in 2015 for prophylaxis of VTE after hip replacement surgery. It is admin-istered as a prodrug, dabigatran etexilate, that is converted to the active form, dabigatran, in the liver. The half-life ranges from 12 to 17 hours; it is therefore administered once daily for prophylaxis and twice daily for VTE therapy. Absorption is not dietary dependent, and no drug level monitoring is required. Dabigatran is metabolized in the kidney, and dose adjustment is required for renal insufficiency. Data on use in obese patients is limited; therefore, use is not recommended for patients with a body mass index ≥40 kg/m2 or ≥120 kg.46 Dyspepsia is a com-mon side effect that may limit


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Surgery_Schwartz. Data on use in obese patients is limited; therefore, use is not recommended for patients with a body mass index ≥40 kg/m2 or ≥120 kg.46 Dyspepsia is a com-mon side effect that may limit use in some patients.47 Dabigatran may be reversed with idarucizumab in emergent situations.48 It is contraindicated in patients with mechanical heart valves.Direct factor Xa inhibitors, which are comprised of the oral agents rivaroxaban, apixiban, and edoxaban, are FDA approved for treatment in VTE and prophylaxis for recurrent VTE. Additionally, rivaroxoban and apixiban are approved by the FDA for VTE prophylaxis following knee and hip replace-ment surgery. These medications function by inactivating cir-culating and thrombus-bound factor Xa. They are metabolized in the kidney (25–35%) and in the liver; therefore, use is not rec-ommended in patients with renal insufficiency (creatinine clear-ance <30 mL/min for rivaroxaban, or <15 mL/min for apixiban and edoxaban) or severe hepatic insufficiency. As


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Surgery_Schwartz. therefore, use is not rec-ommended in patients with renal insufficiency (creatinine clear-ance <30 mL/min for rivaroxaban, or <15 mL/min for apixiban and edoxaban) or severe hepatic insufficiency. As with the oral DTI, dabigatran, data on use in obese patients is limited; there-fore, use is not recommended in these patients. Additionally, these agents are contraindicated in pregnancy. There are no specific reversal agents available for direct factor Xa inhibi-tors. For severe cases of hemorrhage, indirect partial reversal may be achieved with use of prothrombin complex concentrate administration.49Rixaroxaban has a half-life of 7 to 17 hours. Therapy does not require monitoring. Prophylactic dosing is 10 mg once daily, and therapeutic dosing is 15 mg twice daily for 21 days, fol-lowed by 20 mg once daily thereafter.Apixiban has a half-life of 5 to 9 hours. Therapy does not require monitoring, and there are no dietary restrictions. If monitoring is desired in situations of bleeding or


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Surgery_Schwartz. 20 mg once daily thereafter.Apixiban has a half-life of 5 to 9 hours. Therapy does not require monitoring, and there are no dietary restrictions. If monitoring is desired in situations of bleeding or concern for subor supratherapeutic dosing, serum anti-Xa levels can be obtained. Prophylactic dosing is 2.5 mg twice daily, and thera-peutic dosing is 10 mg daily for 7 days, followed by 5 mg twice daily thereafter.Edoxaban has a half-life of 10 to 14 hours. Therapy does not require monitoring. Typical dosing is 60 mg once daily, and 30 mg once daily if creatinine clearance ranges from 15 to 50 mL/min, or body weight ≤60 kg.Vitamin K antagonists, which include warfarin and other coumarin derivatives, are the traditional mainstay of long-term antithrombotic therapy in patients with VTE. Warfarin inhib-its the γ-carboxylation of vitamin K–dependent procoagulants (factors II, VII, IX, and X) and anticoagulants (proteins C and S), resulting in formation of less functional proteins.


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Surgery_Schwartz. Warfarin inhib-its the γ-carboxylation of vitamin K–dependent procoagulants (factors II, VII, IX, and X) and anticoagulants (proteins C and S), resulting in formation of less functional proteins. Warfarin usu-ally requires several days to achieve full effect because normal circulating coagulation proteins must first undergo their normal degradation. Factors X and II have the longest half-lives, in the range of 36 and 72 hours, respectively. A steady-state concen-tration of warfarin is usually not reached for 4 to 5 days.Warfarin therapy is monitored by measuring the INR, calculated using the following equation:INR = (patient prothrombin time/laboratorynormal prothrombin time)ISIwhere ISI is the international sensitivity index. The ISI describes the strength of the thromboplastin that is added to activate the extrinsic coagulation pathway. The therapeutic target INR range is usually 2.0 to 3.0, but the response to warfarin is variable and depends on liver function, diet, age, and


Surgery_Schwartz

Surgery_Schwartz. is added to activate the extrinsic coagulation pathway. The therapeutic target INR range is usually 2.0 to 3.0, but the response to warfarin is variable and depends on liver function, diet, age, and concomitant medica-tions. In patients receiving anticoagulation therapy without con-comitant thrombolysis or venous thrombectomy, the vitamin K antagonist may be started on the same day as the initial paren-teral anticoagulant, usually at doses ranging from 5 to 10 mg. Smaller initial doses may be needed in older and malnourished patients, in those with liver disease or congestive heart failure, and in those who have recently undergone major surgery.49The recommended duration of warfarin antithrombotic therapy is stratified based on whether the DVT was provoked or unprovoked, whether it was the first or a recurrent episode, where the DVT is located, and whether malignancy or thrombophilia is present. Current ACCP recommendations for duration of warfarin therapy are summarized in Table


Surgery_Schwartz

Surgery_Schwartz. the first or a recurrent episode, where the DVT is located, and whether malignancy or thrombophilia is present. Current ACCP recommendations for duration of warfarin therapy are summarized in Table 24-4.In patients with proximal DVT, several randomized clini-cal trials have demonstrated that shorter-term antithrombotic therapy (4 to 6 weeks) is associated with a higher rate of VTE recurrence than 3 to 6 months of anticoagulation.50-52 In these trials, most of the patients with transient risk factors had a low rate of recurrent VTE, and most recurrences were in patients with continuing risk factors. The ACCP recommendation, there-fore, is that 3 months of anticoagulation are sufficient to prevent 3Brunicardi_Ch24_p0981-p1008.indd 98922/02/19 3:01 PM 990SPECIFIC CONSIDERATIONSPART IITable 24-4Summary of American College of Chest Physicians recommendations regarding duration of long-term antithrombotic therapy for deep vein thrombosis (DVT)CLINICAL SUBGROUPANTITHROMBOTIC TREATMENT


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Surgery_Schwartz. 24-4Summary of American College of Chest Physicians recommendations regarding duration of long-term antithrombotic therapy for deep vein thrombosis (DVT)CLINICAL SUBGROUPANTITHROMBOTIC TREATMENT DURATIONFirst episode DVT/transient risk/surgeryVKA or LMWH for 3 monthsFirst episode DVT/unprovokedVKA or LMWH for 3 monthsConsider for long-term therapy if:• Proximal DVT• Minimal bleeding risk• Stable coagulation monitoringDistal DVT/unprovoked• Symptomatic• Asymptomatic and no risk factors for progressionVKA for 3 monthsSerial imaging in 2 weeks, if progression VKA for 3 monthsSecond episode DVT/unprovokedDVT and cancerVKA for extended therapyLMWH for extended therapy over VKALMWH = low molecular weight heparin; VKA = vitamin K antagonist.Data from Kearon C, Akl EA, Comerota AJ, et al: Antithrombotic therapy for VTE disease: Antithrombotic Therapy and Prevention of Thrombosis, 9th ed: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines, Chest. 2012 Feb;141(2


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Surgery_Schwartz. therapy for VTE disease: Antithrombotic Therapy and Prevention of Thrombosis, 9th ed: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines, Chest. 2012 Feb;141(2 Suppl): e419S-e496S.recurrent VTE in patients with DVT occurring around the time of a transient risk factor (e.g., hospitalization or orthopedic or major general surgery).In contrast to patients with thrombosis related to transient risk factors, patients with unprovoked VTE are much more likely to develop recurrence (rates as high as 40% at 10 years). In this latter group of patients, numerous clinical trials have compared 3 to 6 months of anticoagulation therapy with extended-duration warfarin therapy, both at low intensity (INR of 1.5 to 2.0) and at conventional intensity (INR of 2.0 to 3.0).53-55 In patients with idiopathic DVT, extended-duration antithrombotic therapy is associated with a relative reduction in the rate of recurrent VTE by 75% to >90%. In addition, conventional-intensity


Surgery_Schwartz

Surgery_Schwartz. In patients with idiopathic DVT, extended-duration antithrombotic therapy is associated with a relative reduction in the rate of recurrent VTE by 75% to >90%. In addition, conventional-intensity warfarin reduces the risk even further compared with low-intensity war-farin (0.7 events per 100 person-years vs. 1.9 events per 100 person-years) without an increase in bleeding complications.56In patients with VTE in association with a hypercoagulable condition, the optimal duration of anticoagulation therapy is influ-enced more by the clinical circumstances at the time of the VTE (idiopathic vs. secondary) than by the actual presence or absence of the more common thrombophilic conditions. In patients with VTE related to malignancy, increasing evidence suggests that longer-term therapy with LMWH (up to 6 months) is associated with a lower VTE recurrence than treatment using conventional vitamin K antagonists.57,58 The primary complication of warfarin therapy is hemorrhage, and the risk is


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Surgery_Schwartz. (up to 6 months) is associated with a lower VTE recurrence than treatment using conventional vitamin K antagonists.57,58 The primary complication of warfarin therapy is hemorrhage, and the risk is related to the magnitude of INR prolongation. Depending on the INR and the presence of bleeding, warfarin anticoagulation may be reversed by (a) omit-ting or decreasing subsequent dosages, (b) administering oral or parenteral vitamin K, or (c) administering fresh frozen plasma, prothrombin complex concentrate, or recombinant factor VIIa.49Warfarin therapy rarely may be associated with the devel-opment of skin necrosis and limb gangrene. These conditions occur more commonly in women (4:1), and the most commonly affected areas are the breast, buttocks, and thighs. This com-plication, which usually occurs in the first days of therapy, is occasionally, but not exclusively, associated with protein C or S deficiency and malignancy. Patients who require continued anticoagulation may restart


Surgery_Schwartz

Surgery_Schwartz. usually occurs in the first days of therapy, is occasionally, but not exclusively, associated with protein C or S deficiency and malignancy. Patients who require continued anticoagulation may restart low-dose warfarin (2 mg) while receiving concomitant therapeutic heparin. The warfarin dosage is then gradually increased over a 1to 2-week period.49Systemic and Catheter-Directed Thrombolysis. Patients with extensive proximal, iliofemoral DVT may benefit from systemic thrombolysis or catheter-directed thrombolysis (CDT). CDT appears to be more effective (see later in chapter) and potentially reduces acute congestive lower extremity symp-toms more rapidly than anticoagulation alone and decreases the development of PTS.Several thrombolytic agents are available, including strep-tokinase, urokinase, alteplase (recombinant tissue plasminogen activator), reteplase, and tenecteplase. All share the ability to con-vert plasminogen to plasmin, which leads to the degradation of fibrin. They differ


Surgery_Schwartz

Surgery_Schwartz. alteplase (recombinant tissue plasminogen activator), reteplase, and tenecteplase. All share the ability to con-vert plasminogen to plasmin, which leads to the degradation of fibrin. They differ with regard to their half-lives, their potential for inducing fibrinogenolysis (generalized lytic state), their poten-tial for antigenicity, and their FDA-approved indications for use.Streptokinase is purified from β-hemolytic Streptococcus and is approved for the treatment of acute myocardial infarction, PE, DVT, arterial thromboembolism, and occluded central lines and arteriovenous shunts. It is not specific for fibrin-bound plas-minogen, however, and its use is limited by its significant rates of antigenicity. Fevers and shivering occur in 1% to 4% of patients.Urokinase is derived from human neonatal kidney cells grown in tissue culture. Currently, it is only approved for lysis of massive PE or PE associated with unstable hemodynamics.Alteplase, reteplase, and tenecteplase all are


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Surgery_Schwartz. human neonatal kidney cells grown in tissue culture. Currently, it is only approved for lysis of massive PE or PE associated with unstable hemodynamics.Alteplase, reteplase, and tenecteplase all are recombinant variants of tissue plasminogen activator. Alteplase is indicated for the treatment of acute myocardial infarction, acute ischemic stroke, and acute massive PE. However, it often is used for CDT of DVT. Reteplase and tenecteplase are indicated only for the treatment of acute myocardial infarction.Systemic thrombolysis was evaluated in numerous older prospective and randomized clinical trials, and its efficacy was summarized in a recent Cochrane Review.59 In 12 studies involving over 700 patients, systemic thrombolysis was associ-ated with significantly more clot lysis (relative risk [RR] 0.24 to 0.37) and significantly less PTS (RR 0.66). However, venous function was not significantly improved. In addition, more bleeding complications occurred (RR 1.73).In an effort to minimize


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Surgery_Schwartz. [RR] 0.24 to 0.37) and significantly less PTS (RR 0.66). However, venous function was not significantly improved. In addition, more bleeding complications occurred (RR 1.73).In an effort to minimize bleeding complications and increase efficacy, CDT techniques were developed for the treat-ment of symptomatic primarily iliofemoral DVT. With catheterdirected therapy, venous access may be achieved through percutaneous catheterization of the ipsilateral popliteal vein, retrograde catheterization through the contralateral femoral vein, or retrograde cannulation from the internal jugular vein. Multi–side-hole infusion catheters, with or without infusion wires, are used to deliver the lytic agent directly into the throm-bus. Lytic agents may be administered alone or, now more commonly, in combination with catheter-based methods to Brunicardi_Ch24_p0981-p1008.indd 99022/02/19 3:01 PM 991VENOUS AND LYMPHATIC DISEASECHAPTER 24ABFigure 24-9. Preoperative computed tomography imaging and


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Surgery_Schwartz. with catheter-based methods to Brunicardi_Ch24_p0981-p1008.indd 99022/02/19 3:01 PM 991VENOUS AND LYMPHATIC DISEASECHAPTER 24ABFigure 24-9. Preoperative computed tomography imaging and intraoperative photo demonstrating erosion of IVC filter through the IVC wall.physically break up the clot—so-called pharmacomechanical thrombolysis. One commonly used device to perform phar-macomechanical thrombolysis is the AngioJet, which utilizes pulsed injection of thrombolytic via a percutaneously inserted catheter followed by active aspiration to remove the thrombus.The efficacy of CDT for the treatment of symptomatic iliofemoral DVT has been reported previously in a large, multi-center, randomized control trial. Two-hundred and nine patients with proximal DVT identified within 21 days of onset of symp-toms were assigned to conventional anticoagulant therapy vs. conventional anticoagulant therapy plus CDT. In the CDT group, placement of a venous stent was permitted for any identified iliac


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Surgery_Schwartz. of symp-toms were assigned to conventional anticoagulant therapy vs. conventional anticoagulant therapy plus CDT. In the CDT group, placement of a venous stent was permitted for any identified iliac vein stenotic lesion. At 6 months, iliac vein patency was signifi-cantly improved in the thrombolysis group (65.9% vs. 47.4%). At 2 years, in the CDT group, there was an absolute risk reduc-tion of nearly 15% for development of PTS, translating to a num-ber needed to treat of seven patients to prevent one case of PTS.60 However, these results were, in part, contradictory to the results reported the more recent Acute Venous Thrombosis: Throm-bus Removal with Adjunctive Catheter-Directed Thrombolysis (ATTRACT) trial, a prospective, randomized, multicenter trial evaluating nearly 700 patients comparing anticoagulant use with CDT in patients with acute femoropopliteal, and/or iliac vein DVT.61 However, the purpose of this trial was to see if indica-tions for CDT should be extended for isolated


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Surgery_Schwartz. anticoagulant use with CDT in patients with acute femoropopliteal, and/or iliac vein DVT.61 However, the purpose of this trial was to see if indica-tions for CDT should be extended for isolated femoropopliteal DVT (43% of the patients in this study) and therefore, was under-powered to compare treatment efficacy for iliofemoral DVT, which known to have a higher risk of PTS. The study found that PTS occurred with equal frequency in the two groups (47% vs. 48%, P = NS), but patients who were treated with pharmacom-echanical CDT plus anticoagulation were less likely to develop moderate-to-severe PTS than those treated with anticoagulation alone (18% vs. 24%, P = .003). There was no difference between the two groups in quality of life. There was an increase in both overall hemorrhage (4.5% vs. 1.7%) and major hemorrhage (1.7% vs 0.3%) with CDT but no fatal or intracranial hemor-rhage in either cohort. Taken in combination, the findings from these trials support selective use of CDT with


Surgery_Schwartz

Surgery_Schwartz. 1.7%) and major hemorrhage (1.7% vs 0.3%) with CDT but no fatal or intracranial hemor-rhage in either cohort. Taken in combination, the findings from these trials support selective use of CDT with anticoagulation in young patients with acute iliofemoral DVT and anticoagulation alone in the remaining patient with DVT.There are contraindications to thrombolytic therapy. Absolute contraindications include prior history of ischemic or hemorrhagic stroke within 3 months, head trauma within 3 months, neurologic surgery within 6 months, known intra-cranial neoplasm, internal bleeding within 6 weeks, active or known bleeding disorder, traumatic cardiopulmonary resuscita-tion within 3 weeks or suspected aortic dissection. Fortunately, serious remote bleeding is uncommon, and intracranial hem-orrhage rarely occurs. The majority of bleeding complications are limited to the venous access site. Symptomatic pulmonary embolism occurs uncommonly and is very rarely fatal.Inferior Vena Caval


Surgery_Schwartz

Surgery_Schwartz. hem-orrhage rarely occurs. The majority of bleeding complications are limited to the venous access site. Symptomatic pulmonary embolism occurs uncommonly and is very rarely fatal.Inferior Vena Caval Filters. Since the introduction of the Kimray-Greenfield filter in the United States in 1973, numerous vena caval filters have been developed. Although the designs are variable, they all are designed to prevent pulmonary emboli, while allowing continuation of venous blood flow through the IVC. Early filters were placed surgically through the femoral vein. Currently, less invasive techniques allow percutaneous filter placement through a femoral vein, internal jugular vein, or a peripheral vein under fluoroscopic or ultrasound guidance.Placement of an IVC filter is indicated for patients who have manifestations of lower extremity VTE and absolute contraindications to anticoagulation, those that have a bleeding complication from anticoagulation therapy of acute VTE, or those who develop


Surgery_Schwartz

Surgery_Schwartz. have manifestations of lower extremity VTE and absolute contraindications to anticoagulation, those that have a bleeding complication from anticoagulation therapy of acute VTE, or those who develop recurrent DVT or PE despite adequate anticoagula-tion therapy and for patients with severe pulmonary hypertension.When possible, anticoagulation therapy should be contin-ued in patients with vena cava filters. The duration of antico-agulation is determined by the underlying VTE and not by the presence of the IVC filter itself. Practically speaking, however, many patients who require an IVC filter for recurrent VTE are the same ones who would benefit most from indefinite antico-agulation. In patients who are not able to receive anticoagulants due to recent surgery or trauma, the clinician should continually reassess if anticoagulation may be started safely at a later date.Placement of permanent IVC filters has been evaluated as an adjunct to routine anticoagulation in patients with proximal