Tracy Minichiello, M.D.Associate Professor of Medicine

University of California, San FranciscoChief, SF VA Anticoagulation & Thrombosis Service

Thromboembolism Q&A: Cases and Controversies

CASE #1 A 55 year old woman being treated for osteomyelitis of the spine develops right upper extremity swelling. U/S reveals a DVT in the subclavian and axillary vein. She has a PICC line in that arm. How do you manage this?

a.Does she need anticoagulation?b.She will need another 3 weeks of IV

antibiotics. Do you remove the PICC Line?

Venous thrombo

sis

Yes•Removal after fibrinolysis•Antibiotics•Anticoagulation if no contraindication•Elevate involved extremity

Septicthrombophlebitis?

Severelysymptomatic?

No

If SVCsyndrome or severesymptoms & lowbleeding risk

Considerthrombolysis

Yes

•Remove catheter•Anticoagulate

NoCatheterneeded?

No

•Remove catheter•Anticoagulate

Yes

•Keep catheter•Anticoagulate

Symptomsresolved?

No

Other accesssites available?

•Remove catheter•Place new catheter•Anticoagulate

•Keep catheter•Anticoagulate

Yes

No Considerthrombolysis

Yes

Management of catheter‐related venous thrombosisAnticoagulation generally recommended for 3 months after catheter removal

Upper Extremity DVT

CASE #2

A 45 year old man presents with complaints of moderate but persistent calf pain and swelling. He was kicked playing soccer a five days ago and symptoms have developed since then. Ultrasound shows DVT in the posterior tibeal vein. What do you recommend?

NEW CHEST GUIDELINESIn patients with acute isolated distal DVT of the leg and without severe symptoms or risk factors for extension, we suggest serial imaging of the deep veins for 2 weeks over initial anticoagulation (Grade 2C).CHEST 2012

ISOLATED DISTAL DVTant/post tibeal, peroneal

TREATMENTLOW RISKu/s 1-2 weeks and

treat only if extends proximally

HIGH RISKtreatment same as proximal DVT

HIGH RISK + d-dimer severe symptoms cancer VTE history no reversible provoking

factor hospitalized near proximal veins > 5 cm long, mult

veins, > 7 mm

CASE #3

A 55 year-old man presents with pleuritic chest pain. His BP is 120/70, HR 105, RR is 18, and his O2 sat is 97%. His physical exam is unremarkable. A chest CT shows multiple pulmonary emboli. ECG is normal.

CASE #3

What is this patient's risk of early mortality related to PE?

What anticoagulant regiman will you start and when?

Will he be admitted and if so for how long?

Pulmonary Embolism Severity Index

Risk Factor points Age age Male 10 Cancer 30 Heart failure 10 Chronic lung disease

10

HR > 110 20 SBP < 100 mmHG 20 RR >30 20 Temp < 36 20 Δ mental status 60 O2 sat <90% 20

Aujesky et al Eur Heart Journal 2006

class Points 30 day mortality

I 0-65 <1.7% II 66-85 <3.5% III 86-105 <7.1% IV 106-125 4-11% V >125 10-25%

Simplified Pulmonary Embolism Severity Index

Risk Factor points Age 1 if > 80 Cancer 1

Heart failure lung disease

1

SBP < 100 mmHG 1

O2 sat <90% 1

Severity class Points 30 day mortality LOW 0 1% HIGH 1 or more 10%

Jimenez, D. et al. Arch Intern Med 2010

Case #3a

His PESI score is 65, placing him in Class I, very low risk of PE related mortality. You decide to discharge him to home. He weighs 100 kg. He has CKD with CrCl of 39 ml/min. What dose of enoxaparin do you recommend?

Anticoagulation for VTEUse UFH preferentially

Immediate risk of bleeding

Renal Failure Extremes of weight Massive PE,submassive

PE when considering thrombolysis

CHEST 2012

LMWH preferred agent for acute treatment VTE

Enoxaparin Dosing in CKD

Treatment Doses Enoxaparin

1st 48hrs: 1mg/kg q12hrs* Maintenance: dose adjust based on renal function*:  

Est CrCl(ml/min) 

Fraction of usual daily dose 

10‐19 0.320‐29 0.430‐39 0.540‐49 0.6≥ 50 1

 

Barras MA, Clin Pharmacol Ther. 2008; Barras MA, Ther Drug Monit. 2010

Enoxaparin Dosing in CKD

Barras MA, Clin Pharmacol Ther. 2008; Barras MA, Ther Drug Monit. 2010

 

Endpoints Individualized arm N=46 

Conventional arm N= 54 

Pvalue

Therapeutic Xa levels  (0.5‐1)

69.9%  42.6% 0.02

SupratherapeuticXa  (> 1) 

9.3%  37.1% 0.02

Subthreapeutic Xa levels  (<0.5) 

12.9%  15.7% 0.97

Endpoints  Individualized N=46 

Conventional N= 54 

P‐value

Any bleedig   1 (2%) 9 (15%) 0.03Composite bleed/bruise  

6 (12%) 21 (40%) 0.003

 

CASE # 4

A 68 year old woman falls and fractures her hip. She is in CHF on admission so OR time is delayed. On HD #3 she becomes acutely short of breath and is found to have PE and DVT. How do you manage her anticoagulation perioperatively?

IVC Filter IndicationsIndication for IVC Filter Placement

ACCP( 1)

AHA (2)

British Committee for Standards in Hematology (3)

Thrombosis Interest Group of Canada (4)

Acute VTE and contraindication to anticoagulation

YES YES YES YES If proximal DVT present

VTE despite anticoagulation

NO YES MAYBE High intensity oral anticoagulation or LMWH should be considered prior to placement of filter

NO Anticoagulation should be intensified or alternative agent started. IVC filter will not prevent progression

Preoperatively in patients who have had recent VTE (within one month) and must have anticoagulation interrupted for surgery

____ ___ YES (VTE within 4 weeks prior to surgery)

YES (VTE within 2 weeks prior to major surgery)

IVC Filter Indications

Indication for IVC Filter Placement

ACCP( 1)

AHA (2)

British Committee for Standards in Hematology (3)

Thrombosis Interest Group of Canada (4)

Proximal DVT in patient with poor cardiopulmonary reserve

____ YES ___ There is no agreement on definition of poor reserve

Free-floating thrombus

____ ___ NO NO

Thrombolysis with proximal DVT

____ ___ NO NO

Primary prophylaxis in selected high risk patients (surgical, trauma etc)

NO ___ ____ NO

IVC Filters

PREPIC STUDY GROUP, Circulation 2005; Decousus NEJM 1998

Filter No Filter

PE@ 12 days

1% 5%

DVT @ 2 years

20% 11%

PE@ 2 years

3.4%(ns) 6.3%

PREPIC STUDY PREPIC 8 yr FOLLOW UP

DVTHR 1.52

PEHR 0.32

No survival benefit

NEW CHEST GUIDELINESIVC filters should only be placed in acute DVT who cannot tolerate blood thinners because of active bleeding or a high risk for bleeding. “We do not consider permanent IVC filter indication for extended anticoagulation”.CHEST 2012

How long will you recommend these patients stay on

anticoagulation? 55 yo man with

unprovoked PE?

3 months6 months12 monthsIndefinitely

68 yo woman with provoked PE?3 months6 months12 monthsIndefinitely

Risk of VTE Recurrence After Cessation of VTE

Risk factor 1st yr Next 5 yrs

Distal DVT 3% (6%) <10%

Major-transient

3% 10%

Minor-transient

5-6% 15%

Unprovoked At least 10% 30%

Recurrent > 10% > 30%

Kearon, Blood 2005

Diseases Associated with VTE

Systemic

disease

Clinical Features Diagnostic Data

IBD Bloody diarrhea, aphthous ulcers,

arthritis, rash

Histologic analysis of

intestinal biopsy

specimens

Nephrotic

syndrome

Periorbital edema, peripheral edema,

HTN, hypercholesterolemia

Urine protein analysis

Behcets Oral ulcers, genital ulcers,

ophthalmologic issues

--

(P. Vera/ ET Pruritis, plethora CBC, JAK-2 mutation

Systemic disease Clinical Features Diagnostic Data

Sickle cell disease Anemia, sickle crises Evaluation of the blood smear,

hemoglobin electrophoresis

Antiphospholipid

antibody

syndrome

Livedo, arthritis, rash Lupus anticoagulant, ELISA for

anticardiolipin antibody IgG and

IgM (assess 3 months after acute

event)

Cancer Weight loss, night

sweats

CBC, LFTS, PSA, pap smear,

routine cancer screening

Paroxysmal

nocturnal

hemoglobinuria

Hemolytic anemia CBC, Flow cytometry for CD55,

CD59

Pregnancy Amenorrhea Urine pregnancy test (all women of

childbearing age)

Copyright restrictions may apply.

Iorio, A. et al. Arch Intern Med 2010;170:1710-1716.

Recurrence Rate After Transient Risk Factor

3.3% in 1st yr

6.6% in 1st 2 yrs

Guidelines for Duration of Anticoagulation for VTE

Indication

8th ACCP guidelines

2012AHA 2010

ASH recommendations2008

First episode of VTE secondary to a transient risk factor

3 months (Grade 1B).

3 months (Class I Level A)

3 months

First episode of idiopathic (unprovoked) VTE

At least 3 months, prefer long-term treatment if risk/benefit ratio ok (Grade 2B).

At least 6 months, consider indefinite(Class I Level A)

6 months

Recurrent VTE Long term(Grade 1B).

IndefiniteClass I Level A).

Long term if APLS, AT deficiency or recurrence

Kearon et al CHEST suppl Feb 2012;Jaff et al Circulation 2011; Bounsameaux H et al Hematology 2009

Copyright ©2008 American Society of Hematology. Copyright restrictions may apply.

Siragusa, S. et al. Blood 2008

Residual Vein Thrombosis & VTE Recurrence

RVO+AC 19%

No RVO 1 %

RVO-AC 27 %

Recurrence rate

Palareti G et al. N Engl J Med 2006

Management Trial Using D-dimer Results to Determine Duration of Anticoagulation

Eichinger, Circulation 2010

Vienna Prediction Model for Recurrent VTE

Clinical Decision Rule Clinical predictors

Leg red or swollen or hyperpigment 5-7 mos after event

D-dimer >250 ug/L on ACBMI >30kg/m2Age> 65

Female patients with 0-1 risk factor had recurrence risk of 1.6%: ≥2 = 14%

Rodgers et al CMAJ August 2008

Risk Score For Predicting Recurrent VTE

DASHD-dimerAge > 50Sex-maleHormonal therapy

Score Annualized Risk≤1 3.1%2 6.4%≥3 12.3%

Tosetto A et al J Thromb Haemost. 2012

Risk Score For Predicting Recurrent VTE

DASH POINTSd-dimer elevated after completion of blood thinner

+2

age > 50 1male 1female with VTE on hormonal therapy

-2

SCORE ANNUALIZED RISK

≤1 3.1%2 6.4%≥3 12.3%

Tosetto A et al J Thromb Haemost. 2012

Clinical presentation predicts likelihood and type

of recurrence Distal (calf vein thrombosis)

Low risk of recurrence/PE Proximal- nearly 5 fold increased

recurrence risk over distal PE vs. DVT

Patients presenting with PE are 3x more likely to suffer recurrent PE than those presenting with DVT

Baglin T etJ Thromb Haemost. 2010

How long will you recommend these patients stay on

anticoagulation? 55 yo man with

unprovoked PE?

3 months6 months12 monthsIndefinitely

68 yo woman with provoked PE?3 months6 months12 monthsIndefinitely

Case 5c

Do either of these patients need a work up for laboratory thrombophilia?

Impact of Thrombophilia on Recurrence Risk

Patient group Recurrence of VTE per Yeartotal 2.6%1 thrombophilia defect 2.5%Iniitial VTE provoked 1.8%Initial VTE unprovoked 3.3%Unprovoked with thrombophilia 3.4%Unprovoked without thrombophilia

3.2%

Christiansen JAMA 2005

Shulman Amer j Med 1998

Impact of Acute Thrombosis & Anticoagulation on Thrombophilia Testing

increasedFactor VIII level

decreasedAntithrombinlevel

decreasedNo effectdecreasedProtein C, S

prolongedprolongedLupus anticoagulant

Anticardiolipinantibodies

WarfarinHeparinAcute VTEtest

no effectno effectincreasedFactor VIII level

increaseddecreaseddecreasedAntithrombinlevel

decreasedNo effectdecreasedProtein C, S

prolongedprolongedMay be prolonged

Lupusanticoagulant

no effectno effectMay beelevated

Anticardiolipinantibodies

WarfarinHeparinAcute VTEtest

Laboratory Thrombophilia

Women of childbearing years Patients with suspicion for APLS Strong family history of VTE Patients with recurrent VTE Results will influence therapy

(duration) Unprovoked PE < 50 yo

Individual Bleeding Risk on Anticoagulation

Bleeding Risk Factors Age > 75 Previous GI bleed

with no reversible cause

Previous bleed on warfarin

Renal/hepatic failure Antiplatelet therapy Cancer

Case fatality rate VTE Case fatality rate of

recurrent VTE highest in 1st 3-6 months-11%

Case fatality rate of recurrent VTE decreases after 3-6 months to 3.6%

Carrier Ann Intern Med 2010

Duration of AnticoagulationUnprovoked VTE

ng

riskConsider

indefinite

tx(PE,

male,

thrombophilia)Discuss

patient

preference

No

RVOClinical

prediction

rule:<1

stop

anticoagulation

Measure

D-dimer

at

30days,if

low

okIf

elevated

consider

Restarting

tx

ence

of

RVO

Continue

anticoagulation

and

repeat

U/S

IF DVT Get u/s and measure d-dimer . If d-dimer up continue AC

Aspirin for Prevention of Recurrent VTE.

Becattini C et al. N Engl J Med 2012

Recurrent VTE•ASA 6.6%•Placebo 11.2 %

•↓VTE 40% •No difference in major bleeding

CASE # 6

A 33 year old woman diagnosed with left lower extremity DVT 3 months ago maintained on warfarin present with complaints of pleuritic chest and shortness of breath. A CT angio of the chest reveals new bilateral subsegmental pulmonary emboli.

CASE #6

She reports compliance with her warfarin therapy and has an INR of 2.5 at the time of admission. She is admitted to your service for recurrent VTE. How do you manage this?

VTE Despite Anticoagulation

Medication adherence Antiphospholipid antibody syndrome Cancer DIC/Trousseaus Heparin-induced thrombocytopenia Myeloproliferative disorder Antithrombin deficiency Structural defect

VTE Despite Anticoagulation

Warfarin failureTransition to LMWH then transition to

warfarin with higher target OR continue LMWH

LMWH failureChange to BID dosingIncrease dosing by 20%Follow anti-Xa levels

Treatment of VTE Recurrence in Cancer

Patients

Lee, A ASH Education Book December 4, 2010

CASE #7

69 year old man with history of AFIB, diabetes, hypertension is having total hip arthroplasty. He is on warfarin as an outpatient for stroke prophylaxis. How do you mange his anticoagulation in perioperative period?

Perioperative Management of Anticoagulation

Spyropoulus et al Blood. 2012

Perioperative Management of Anticoagulation

Spyropoulus et al Blood. 2012

Case #8A 60 year old man with hyperlipidemia and hypertension on atenolol, a statin and ASA develops AFIB. His CHADS2 score is 1. You:A) start warfarin for stroke prophylaxisB) continue ASA for stroke prophylaxis

NEW CHEST GUIDELINES

AFIB CHADS2=0 no therapy (2B); CHADS ≥1 anticoagulant (1B);if unsuitable for AC use asa+clopidigrel rather than asa (1B)