Venous 1hromboembo||sm

Llsa k Moores, Mu
AsslsLanL uean for Cllnlcal Sclences
rofessor of Medlclne
1he unlformed Servlces unlverslLy of Lhe PealLh
Sclences
Iacu|ty D|sc|osures
nCnL
Learn|ng Cb[ecnves
Aer Lhls sesslon, learners wlll be able Lo:
LlsL Lhe rlsk facLors for v1L
SLaLe Lhe properues of dlagnosuc Lesung and use Lhls
Lo creaLe a dlagnosuc algorlLhm for uv1 and L
LlsL Lhe recommended LreaLmenL reglmens for
Lhromboembollsm
LlsL Lhe sLraLegles recommended for v1L prevenuon
ln hlgh rlsk pauenLs
V1L -- Acqu|red k|sks
lmmoblllLy/paralysls
Cancer
Ma[or surgery
1rauma
CbeslLy
regnancy
AL/lupus AC
1herapy 8elaLed
CPl/ACS
SLroke
lracLures/surgery LLs
lndwelllng caLheLers
l8u
AcuLe lnammaLory
sLaLes
CCD
1he preva|ence of L |n anents w|th CCD Lxacerbanon
8lzkallah !. eL.al. ChesL,2009,133:786-793
2009 by Amerlcan College of ChesL hyslclans
V1L -- Genenc k|sks
AcuvaLed roLeln C 8eslsLance
A1lll, roLeln C, roLeln S declency
uysbrlnogenemla
lasmlnogen acuvauon dlsorder
AL/lupus anucoagulanL
roLhrombln muLauon
PyperhomocysLelnemla
lnLeresungly, Lhrombophlllas lncrease rlsk of lncldenL
v1L, buL do noL necessarlly predlcL recurrenL dlsease!
D|agnos|s
Cllnlcal slgns non-speclc
C||n|ca| "Gesta|t"
Cllnlclans oen dlsagree
Lxperlence lnuences assessmenL
LsumaLes Lend Lo normallze Lo Lhe cenLer
1he exacL meLhods are dlmculL Lo measure or
reproduce
We||s ku|e for DV1
1 polnL each for:
Acuve cancer
aralysls, paresls, casL
8edrldden > 3 days, ma[or surgery w/ln 12 weeks
1enderness along deep velns
Calf swelllng (3 cm asymmeLry)
AsymmeLrlc plmng edema
CollaLeral superclal velns
rlor uv1
Wells eL al. !AMA 2006, 263:199
We||s ku|e for DV1
AlLernauve dlagnosls aL leasL as llkely as uv1 ---
subLracL 2 polnLs

Plgh probablllLy: 3 or greaLer polnLs
lnLermedlaLe: 1-2 polnLs
Low: 0 or negauve polnLs
Canadian (Wells) Clinical Prediction Score
Variable and Score for PE
Signs and symptoms of DVT 3.0
PE as or more likely than an alternative
diagnosis 3.0
Heart Rate > 100 beats/min 1.5
Immobilization or surgery in previous
4 weeks 1.5
Previous DVT or PE 1.5
Hemoptysis 1.0
Cancer 1.0
1oLal score: <2 low 1, 2-6 moderaLe, >6 hlgh
ulchoLomlzed score: < 4 unllkely, >4 llkely
uesnon 1
?ou are evaluaung a 33 yo woman ln Lhe Lu wlLh an
lnLermedlaLe probablllLy of L. Cx8 ls normal. ?our
nexL sLep should be Lo:
1. CbLaln a v/C Scan
2. CbLaln a C1 anglogram
3. CbLaln a LL uS
4. CbLaln a serum u-ulmer level
D|agnos|s
lf your 1 ls low or lnLermedlaLe:
CbLaln a u-ulmer level
8ased upon hlgh sensluvlLy
SensluvlLy 88 and 90 respecuvely
negauve redlcuve value 99 and 96
negauve Llkellhood 8auo 0.18 and 0.19
nL8 wlLh hlghly sensluve u-ulmer 0.10 and 0.03
NV drops to 92 w|th h|gh 1
Wells, . S. eL al. !AMA 2006,293:199-207.
D-D|mer |n spec|hc popu|anons
u-ulmer can be safely used, when comblned wlLh a
Cu8, ln:
auenLs wlLh recurrenL v1L
Llderly pauenLs
lnpauenLs
**SpeclclLy (and Lhus uullLy) wlll be lower ln Lhese
groups, buL sensluvlLy remalns hlgh
8rulnsLroop L. Lur ! lnL Med 2009, 20:441-46
D-D|mer |n spec|hc popu|anons
u-ulmer cannoL be safely used ln:
auenLs wlLh sympLoms of v1L for greaLer Lhan 14 days
auenLs wlLh suspecLed v1L recelvlng Lherapeuuc heparln
LreaLmenL
auenLs recelvlng oral anucoagulauon Lherapy
8rulnsLroop L. Lur ! lnL Med 2009, 20:441-46
We||s CDk and D-D|mer
MeLa-analysls of prospecuve sLudles LhaL wlLhheld
anucoagulauon ln pauenLs wlLh unllkely Cu8 and
negauve u-ulmer
4 sLudles wlLh over 3800 pauenLs--1660 pauenLs (28)
had L excluded wlLhouL lmaglng
ooled lncldence of v1L ln Lhe subsequenL 3 monLhs
0.34 (0.03-0.96)
laLal L posslble 0.10
ooled nv of Lhls sLraLegy 99.7
asha S. 1hromb 8es 2010, 123:e123-127
D|agnos|s
kemember that spec|hc|ty |s |ow
SpeclclLy 72 and 38 respecuvely
osluve predlcuve value 17 and 32
osluve L8 3.3 and 2.1
An abnormal u-ulmer does noL mean you need Lo
rule ouL v1L!!!! ?our cllnlcal susplclon should dlcLaLe
LhaL declslon
D|agnos|s
ln pauenLs wlLh elLher Plgh 1 or abnormal u-
ulmer level, proceed Lo dlagnosuc lmaglng
uesnon 2
?ou are noued by Lhe lab LhaL Lhe u-ulmer level ln
your pauenL ls abnormal. ?our nexL sLep should be
Lo:
1. CbLaln a v/C scan
2. CbLaln LL uS
3. CbLaln C1A
4. no furLher Lesung and begln anucoagulauon for a L
Imag|ng: DV1
Compresslon ulLrasonography - cllnlcal gold
sLandard
Ind|rect C1 venography [ust as accurate
oo|ed sens|nv|ty 96
oo|ed spec|hc|ty 9S
CLher LesLs: M8l, brlnogen scannlng, lmpedance
pleLhysmography, accuLecL
1homas SM eL al. Clln 8adlol 2008, 63:299-304
Imag|ng: L
venulauon/erfuslon scannlng: mosL useful wlLh
normal Cx8 or conLrasL allergy/conLralndlcauon
Compresslon uS lf slgns/sympLoms of uv1 (maybe)
ulglLal subLracuon anglography - hlsLorlc gold
sLandard
C1 anglography - currenL cllnlcal gold sLandard
SLeln eL al. n Lngl ! Med 2006,334:2317-2327
Accuracy of C1A ln Lhe ulagnosls of L from lCLu ll
SLeln eL al. n Lngl ! Med 2006,334:2317-2327
Accuracy of C1A ln Lhe ulagnosls of L from lCLu ll
Mos lC. ! 1hromb PaemosL 2009, !un 22 epub
lncldence of v1L aL 3 MonLhs
ln pauenLs wlLh lndlcauon for C1A
CUS
no longer needed as safeLy neL for dx of cloLs mlssed
on MuC1
MlghL be useful ln deLecung v1L and avoldlng
radlauon of C1 (especlally ln pauenLs wlLh slgns/
sympLoms of uv1, conLralndlcauons Lo C1) or ln
Lhose wlLh non-dlagnosuc v/C scan
Indeterm|nate C1A
Mouon arufacL, conLrasL enhancemenL
We ldenued 327 pauenLs from 8 sLudles
lndeLermlnaLe C1, no furLher sLudles, no 8x
3 monLh recurrenL v1L raLe 16.2
8e careful Lo dlsungulsh negauve from non-
dlagnosuc scan
C1A kad|anon Lxposure
lncreased rlsk of breasL cancer, esumaLed LhaL .4 of
all cancers ln uS relaLed Lo radlauon from C1
Should alm Lo:
8educe radlauon dose
use oLher opuons rsL (CuS ln pLs wlLh leg sympLoms, v/C
wlLh normal Cx8)
uecrease Lhe number of C1As performed (use L8C, Cu8
and u-ulmer)
C1A vs V] |n suspected L
8andomlzed, mulucenLer, conLrolled, non-lnferlorlLy
Anderson, u. 8. eL al. !AMA 2007,298:2743-2733.
uullLy
646/694 C1A were dlagnosuc (10 lnadequaLe, 38 noL
done)
322/712 v/C scans dlagnosuc (386 non-dlagnosuc, 4 noL
done)
ln more recenL managemenL sLudy only 11 of pauenLs
needed C1A when v/C and CuS done rsL
V] Scann|ng: Sn|| a||ve?
Plgh nv and should be consldered ln:
CuLpauenL wlLh low or hlgh 1 and normal Cx8
auenL wlLh conLrasL allergy or renal fallure
?oung women wlLh normal Cx8
?regnancy
lollow-up
Lval for pulmonary P1n
SLC1 lmaglng/Lhrombovlew may lncrease uullLy/
accuracy
8eld !P eL al. Lur ! nucl Med Mol lmaglng 2009, 36:303-21
C||n|ca| Imp||canons
SLraLegles LhaL employ 1 assessmenL, u-ulmer
Lesung, and a non-lnvaslve lmaglng sLudy are safe
C1A appears Lo have greaLer dlagnosuc uullLy, buL
aL Lhe expense of lncreased radlauon and exposure
Lo conLrasL
v/C scannlng should sull have a role, suggesL ln
pauenLs wlLh normal basellne Cx8
non-dlagnosuc v/C wlLh normal ulLrasound also excludes
v1L, buL requlres Lwo LesLs
Cu8
L unllkely L Llkely
u-ulmer
normal no 8x
Abnormal
nexL CharL
L Llkely
Abnormal u-ulmer
Cx8
v/C*
normal
Slgns/Sx uv1?
CuS
?es
Abnormal Cx8/ AsympLomauc
Lower exLremlues
MuC1
no 8x
AC#
AC
no 8x
non-ux
normal
L
Plgh rob
normal
V1L -- 1reatment
Coals of shorL-Lerm LreaLmenL:
revenL recurrence
LxLenslon
laLal L
revenL long-Lerm compllcauons
LaLe recurrence
osL-Lhrombouc syndrome
C1LP
arenLeral anucoagulauon (heparln, LMWP,
penLasaccharldes) lmmedlaLely
vlLamln k anLagonlsLs long Lerm*
V1LAcute 1reatment
earls
lf uslng lvuP, a welghL-based nomogram should
be used
LMWP and penLasaccharldes have advanLages
8loavallablllLy
redlcLable doslng
Lower Pl1 rlsk
uecreased need for monlLorlng
8ed resL ls noL recommended for uv1
Convennona| Anncoagu|ants
Iactor Ik
Iactor k
Iactor VII
Iactor II
rothromb|n
I|br|nogen I|br|n
AnuLhrombln
ulP, (LMWP)
AnuLhrombln
ulP, LMWP,1ll
ulP, LMWP, penLasacch.
vlLamln k anLagonlsLs:
vlL k dependenL facLors
ll vll, lx, x
Intr|ns|c or Lxtr|ns|c Acnvanon
Iactor ka
Iactor IIa
1hromb|n
Convennona| Anncoagu|ants: L|m|tanons
vlL k AnLagonlsLs
MonlLorlng
Slow onseL/oseL
urug lnLeracuons
narrow Lherapeuuc lndex
uleLary resLrlcuons
Peparlns/enLasaccharldes
arenLeral
CsLeoporosls
Pl1/Pl11
lndlrecL acuon
Idea| Anncoagu|ant
SelecuvlLy for chosen hemosLauc LargeL and Lhrombouc
dlsorder
Cral or parenLeral admlnlsLrauon
no lndlvldual ad[usLmenLs or close monlLorlng
Wlde Lherapeuuc wlndow
8apld onseL/oseL
Mlnlmal food or drug lnLeracuons
Low, non-speclc plasma proLeln blndlng
AblllLy Lo lnhlblL free and cloL-bound facLors
no dosage ad[usLmenL for hepauc or renal fallure
Newer Anncoagu|ants
LxLrlnslc
aLhway
lnLrlnslc aLhway
lacLor vlla
1lssue lacLor
hosphollplds
laLor lxa
lacLor vllla
hosphollplds
lacLor x
lacLor xa
hosphollplds
lacLor va -
lacLor xa
roLhrombln 1hrombln
Ind|rect Iactor ka
Inh|b|tors - Annthromb|n
Iondapar|nux
Idrapar|nux
D|rect Iactor ka
Inh|b|tors
kivoroxobon
4pixobon
D|rect 1hromb|n
Inh|b|tors
n|rud|n
Argatroban
8|va|arud|n
uobiqotron
lacLor lx - lacLor lxa
Anticoagulant Phase III study Clinical setting Comparator Status
Rivaroxaban EINSTEIN PE Confirmed PE with or without symptomatic
DVT
Enoxaparin/VKA Published [46]
EINSTEIN DVT Confirmed DVT without PE Enoxaparin/VKA Published [52]
EINSTEIN EXT Confirmed symptomatic DVT or PE having
undergone 612 months of anticoagulation
Placebo Published [52]
Apixaban AMPLIFY Symptomatic DVT or PE Enoxaparin/VKA Results expected 2013
(NCT00643201)
AMPLIFY-EXT Prevention of VTE recurrence or death in
patients who have undergone intended
treatment for VTE
Placebo Published [54]
Edoxaban* HOKUSAI-VTE Treatment of DVT and/or PE Warfarin Results expected 2013
(NCT00986154)
Dabigatran

RE-COVER VTE treatment Warfarin Published [47]
RE-COVER II Results presented [53]
RE-SONATE Long-term prevention of recurrence after 618
months of VKA therapy
Placebo Published [55]
RE-MEDY Long-term treatment after 36 months of
anticoagulation
Warfarin Published [55]

D|rect Cra| Anncoagu|ants |n V1L
C1Ln
uevelops ln 3-4
Absence of recurrenL L, gradual lncrease ln v8
leads Lo vascular remodellng
8lsk facLors noL well dened
Ma[or cenLral evenL
Pemodynamlc compromlse
uocumenLed Lhrombophllla
v/C ls Lhe screenlng LesL of cholce, deLecuon ls
crlucal
Cutpanent 1reatment of L
ulmonary Lmbollsm SeverlLy lndex (LSl)
11 varlables
Age, male sex, cancer, CPl, chronlc lung dlsease, P8 >110,
S8 < 100, 88 > 30, 1 < 36C, alLered menLal sLaLus, SaC2
<90
olnLs glven for each varlable and added Lo age, dlvlded
lnLo 3 classes by polnLs
very low and low rlsk (Class l and ll) have <2 adverse
ouLcome
Cutpanent 1reatment
Cardlac blomarkers less useful ln ldenufylng low rlsk
LSl has greaLer uullLy when compared wlLh Ceneva
score
Slmplled LSl derlved and exLernally valldaLed
ManagemenL Lrlals needed
uesnon 3
8adlology now calls you Lo say Lhe C1A reveals
emboll ln Lhe rlghL lower and mlddle segmenLal
arLerles. ?ou begln LMWP and coumadln. She asks
how long she needs Lo Lake Lhe coumadln. ?ou Lell
her:
uesnon 3
1. 3 monLhs
2. 6 monLhs
3. 12 monLhs
4. lndenlLely
3. noL enough lnformauon Lo deLermlne Lhls
V1L -- 1reatment
uurauon of Lherapy
3 monLhs ln pauenLs wlLh LranslenL rlsk
AL leasL Lhree monLhs ln unprovoked v1L or Lhose
wlLh conunulng rlsk facLors*
randonl, . eL. al. Ann lnLern Med 1996,123:1-7
1he cumulauve lncldence of recurrenL venous Lhromboembollsm ln
pauenLs wlLh a rsL eplsode of sympLomauc deep venous Lhrombosls
1hrombo|ys|s
SLrepLoklnase, uroklnase, rL-A
none has been proven superlor
uesplLe Lhls, ACC recommends reglmen wlLh shorLesL
lnfuslon ume: rL-A
8leedlng rlsk
ooled analyses suggesL C8 .67 (0.40 - 1.12) for ma[or
bleedlng
8eglsLrles suggesL raLes as hlgh as 20 for ma[or bleedlng
and 3-3 for lCP
1odd !L. CPLS1 2009, 133:1321-1329
1hrombo|ys|s: Lmcacy
Pemodynamlc parameLers
8educed pulmonary pressures and lncreased 8v funcuon
ln rsL 12-36 hours
CaLch-up phenomenon for heparln aL 7 days
MorLallLy
ooled analyses show no beneL for unselecLed pauenLs
(C8 0.89 (0.43-1.78))
Subgroup analyses reveal Lrend Loward beneL ln masslve
L (C8 0.47 (0.20 - 1.10))
no daLa ln submasslve L, buL reglsLrles suggesL hlgher
morLallLy ln Lhls group of pauenLs
Wan s. Clrculauon 2004, 110:744-749
Capsuck 1. Lur 8esp ! 2003, 26:844-874
V1L - 1reatment: 1hrombo|ys|s
AgreemenL
auenLs presenung ln shock should recelve Lhrombolysls
ln absence of conLralndlcauon
auenLs who are hemodynamlcally sLable wlLhouL
evldence of 8v sLraln should nC1
ConLroverslal
auenLs wlLh submasslve L: hemodynamlcally sLable
wlLh evldence of 8v sLraln
lurLher rlsk sLraucauon of Lhls group recommend.
ongolng Luropean Lrlal of over 1000 pauenLs uslng
cardlac blomarkers Lo furLher sLraufy
Conrmed L
Pemodynamlcally
SLable
Pemodynamlcally unsLable
ConLralndlcauon Lo
Lhrombolysls?
nexL CharL
Conslder
embolecLomy
1hrombolysls
?LS nC
Pemodynamlcally sLable L
1roponln
8n
Lchocardlogram/C1A
8v uysfuncuon
osluve 8lomarkers
Severe hypoxemla
SlgnlcanL resldual uv1
LxLenslve/saddle embolus

Conunue anugoagulauon
Conslder Lhrombolysls
normal
Severe Acute L
CLher LreaLmenL opuons
Surglcal embolecLomy
Local/lnLra-Lhrombus Lhrombolysls
CaLheLer fragmenLauon +/- local Lhrombolysls
lvC lLer placemenL
IVC I||ter |acement
AbsoluLe lndlcauons (proven v1L)
8ecurrenL v1L desplLe adequaLe anucoagulauon
ConLralndlcauon Lo anucoagulauon
Compllcauon of anucoagulauon
lnablllLy Lo achleve/malnLaln adequaLe anucoagulauon
kaufman !A. ! vasc lnLerv 8adlol 2006, 17:449-439
IVC I||ter |acement
8elauve lndlcauons (roven v1L)
lllocaval uv1
Large, free-oaung proxlmal uv1
Masslve L LreaLed wlLh Lhrombolyucs/LhrombecLomy
Chronlc L LreaLed wlLh endarLerecLomy
v1L wlLh llmlLed cardloresplraLory reserve
oor compllance wlLh anucoagulauon
Plgh rlsk for compllcauon of anucoagulauon
IVC I||ters
lndlcauons for removable lLer are Lhe same as for
permanenL lLers
auenLs wlLh removable lLers musL be followed closely
Can conslder removal when rlsk accepLably low or when
pauenL can recelve adequaLe prlmary Lherapy
8esume anucoagulauon as soon as feaslble
kaufman !A. ! vasc lnLerv 8adlol 2006, 17:449-439
revennon
8ased upon level of rlsk and rlsk of bleedlng
Low: <10 v1L wlLhouL prophylaxls---early
ambulauon only
ModeraLe: rlsk of v1L 40, mosL general surglcal
pauenLs, medlcal pauenLs aL bedresL, LMWP,
LuuP, fondaparlnux or mechanlcal lf bleedlng rlsk
hlgh
Plgh: orLhopedlc, ma[or Lrauma, splnal cord
ln[ury, LMWP, fondaparlnux, rlvoroxaban, vlL k
anLagonlsL, mechanlcal lf bleedlng rlsk hlgh

Summary
8apld, non-lnvaslve dlagnosls of v1L ls posslble
1reaLmenL opuons wlll llkely grow, currenL declslons
should be based on hemodynamlcs and 8v funcuon
uurauon ls 3 monLhs vs lndenlLe for boLh uv1 and
L
Cur prlmary goal ls prevenuon--- and we need Lo do
Lhls more eecuvely