Venous Venous Thromboembolism: Thromboembolism:

Deep Venous Deep Venous Thrombosis and Thrombosis and

Pulmonary EmbolismPulmonary Embolism2006 Capital Conference2006 Capital Conference

Andrews Air Force BaseAndrews Air Force Base

CDR Kenneth S. Yew MC, USNCDR Kenneth S. Yew MC, USN

Uniformed Services Uniformed Services UniversityUniversity

Edited by Paul SaleebEdited by Paul Saleeb

ObjectivesObjectives

► Recognize common presentations of deep Recognize common presentations of deep venous thrombosis (DVT) and pulmonary venous thrombosis (DVT) and pulmonary embolus (PE)embolus (PE)

► Understand evidence-based diagnostic and Understand evidence-based diagnostic and therapeutic strategies for DVT/PEtherapeutic strategies for DVT/PE

► Understand the role of prevention for Understand the role of prevention for DVT/PE and use of prevention strategiesDVT/PE and use of prevention strategies

Case 1Case 1

► 37 yo moderately obese female on OCP 37 yo moderately obese female on OCP presents to your office with a two day presents to your office with a two day history of painless R leg swelling. She’s history of painless R leg swelling. She’s been elevating her leg several days after been elevating her leg several days after a severe ankle sprain during a mother-a severe ankle sprain during a mother-daughter soccer game.daughter soccer game.

► No prior medical history, recent surgery No prior medical history, recent surgery or weight loss. She is a non-smoker and or weight loss. She is a non-smoker and drinks rarely.drinks rarely.

► Exam is notable for R ankle splint and Exam is notable for R ankle splint and pitting edema in R calf, which is 1.5 cm pitting edema in R calf, which is 1.5 cm larger than the L.larger than the L.

DVT – Epidemiology and DVT – Epidemiology and EtiologyEtiology

► Annual incidence of venous Annual incidence of venous thromboembolism (VTE) is 1/1000thromboembolism (VTE) is 1/1000

► DVT accounts for one half of VTEDVT accounts for one half of VTE► Carefully evaluated, up to 80% of patients Carefully evaluated, up to 80% of patients

with VTE have one or more risk factorswith VTE have one or more risk factors► Majority of lower extremity DVT arise from Majority of lower extremity DVT arise from

calf veins but ~20% begin in proximal veinscalf veins but ~20% begin in proximal veins► About 20% of calf-limited DVTs will About 20% of calf-limited DVTs will

propagate proximallypropagate proximally

DVT – VTE Risk FactorsDVT – VTE Risk Factors

► MalignancyMalignancy► SurgerySurgery► TraumaTrauma► PregnancyPregnancy► Oral contraceptives or Oral contraceptives or

hormonal therapyhormonal therapy► ImmobilizationImmobilization► Inherited Inherited

thrombophilliathrombophillia

► Presence of venous Presence of venous cathetercatheter

► Congestive failureCongestive failure► Antiphospholipid Antiphospholipid

antibody syndromeantibody syndrome► HyperviscosityHyperviscosity► Nephrotic syndromeNephrotic syndrome► Inflammatory bowel Inflammatory bowel

diseasedisease

DVT – Clinical PresentationDVT – Clinical Presentation►Classically = calf pain, Classically = calf pain,

tenderness, swelling, redness tenderness, swelling, redness and Homan’s signand Homan’s sign Overall sens/spec = 3-91%Overall sens/spec = 3-91% Unreliable for diagnostic decisionsUnreliable for diagnostic decisions

►Wells developed and tested a Wells developed and tested a clinical prediction model for DVTclinical prediction model for DVT

Wells PS, Anderson DR, Bormanis J, et al. Value of assessment of pretest probability of deep-vein thrombosis in clinical management. Lancet 1997;350 (9094):1795-8.

DVT – Wells ScoreDVT – Wells Score

► CancerCancer► Paralysis or plaster Paralysis or plaster

immobilizationimmobilization► Bedrest > 3d or Bedrest > 3d or

surgery in past 4 wkssurgery in past 4 wks► Localized tendernessLocalized tenderness

► Entire leg swollenEntire leg swollen► Calf > 3cm larger than Calf > 3cm larger than

unaffected legunaffected leg► Pitting edema greater Pitting edema greater

than unaffected legthan unaffected leg► Collateral superficial Collateral superficial

veinsveins

The following were assigned a point value of 1 if present:

• Alternative diagnosis more likely than DVT = - 2 points• Probability High (≥ 3), Moderate (1-2) or Low (0 or less)• DVT risk: High – 75%, Moderate – 17%, Low – 3%

Wells PS, Andersen DR, Bormanis J et al. Lancet. 1997;350:1795-8

DVT – Case 1DVT – Case 1

►Our patient has 2-3 risk factors (OCP, Our patient has 2-3 risk factors (OCP, +/- immobilization and trauma+/- immobilization and trauma

►Her Wells score gives her a moderate Her Wells score gives her a moderate pretest probability for DVTpretest probability for DVT

►A d-dimer test is performed…A d-dimer test is performed…

DVT – D-DimerDVT – D-Dimer

► Fibrin degradation product elevated in active Fibrin degradation product elevated in active thrombosisthrombosis

► Negative test can help exclude VTENegative test can help exclude VTE► Preferred testPreferred test

Quantitative Rapid ELISA – sensitivity 96/95% for Quantitative Rapid ELISA – sensitivity 96/95% for DVT/PEDVT/PE

Other methods include latex agglutination and Other methods include latex agglutination and RBC agglutination (SimpliRED)RBC agglutination (SimpliRED)

Stein PD, Hull RD, Patel KC, et al. D-dimer for the exclusion of acute venous thrombosis and pulmonary embolism: a systematic review. Ann Int Med. 2004;140(8):589-602

DVT – D-DimerDVT – D-Dimer

► In 283 patients with In 283 patients with suspected DVT, low-suspected DVT, low-moderate Wells DVT moderate Wells DVT score and negative score and negative d-dimer only 1 (NPV d-dimer only 1 (NPV 99.6%) had DVT 99.6%) had DVT over next 3 monthsover next 3 months

Bates SM, Kearon C, Crowther M, et al. Ann Intern Med. 2003;138:787-94

• Sensitive d-dimer testing can rule out DVT in low-moderate risk patients

DVT – Case 1DVT – Case 1

► Our patient has Our patient has a positive a positive quantitative quantitative ELISAELISA

► Unfortunately a Unfortunately a positive d-positive d-dimer is not dimer is not helpful helpful diagnosticallydiagnostically

► An imaging An imaging study is done…study is done…

DVT – ImagingDVT – Imaging

► Available imaging and ancillary Available imaging and ancillary tests:tests: Compression US – first line Compression US – first line

test, high sens/spectest, high sens/spec Venography – gold standardVenography – gold standard MRI – Lower quality MRI – Lower quality

evidence only at presentevidence only at present Impedance Impedance

plesmythography – not in USplesmythography – not in US Complete lower extremity Complete lower extremity

US – experimentalUS – experimental

DVT – Case 1DVT – Case 1

►Compression US negativeCompression US negative►Options include: Options include:

Venography or MRIVenography or MRI Serial compression US – single US done at Serial compression US – single US done at

5-7 days reliably excludes calf-limited DVT5-7 days reliably excludes calf-limited DVT Follow clinically for resolution of Follow clinically for resolution of

symptoms – riskier, no data supporting symptoms – riskier, no data supporting safety of this optionsafety of this option

American Thoracic Society guidelines: The approach to acute venous thromboembolism. Am J Respir Crit Care Med. 1999;160:1043. Fraser JD, Anderson DR. Radiology. 1999;211(1):9-24

Diagnostic algorithm using D-dimer testing and ultrasound imaging in patients with suspected DVT

                                                                                                                                

* Imaging done from proximal veins to calf trifurcation.Reproduced with permission from Scarvelis, D, Wells, P. Diagnosis and treatment of deep-vein thrombosis. CMAJ 2006; 175:1087. Copyright © 2006 Canadian Medical Association.

Case 2Case 2

► The patient in Case 1 elected to be followed The patient in Case 1 elected to be followed clinically. She returned to clinic 3 days later clinically. She returned to clinic 3 days later with persistent swelling, but no new with persistent swelling, but no new symptomssymptoms

► She was to return the following week, but She was to return the following week, but instead you are called to the ER 10 days instead you are called to the ER 10 days later after she presents with acute onset of later after she presents with acute onset of dyspnea and pleuritic chest paindyspnea and pleuritic chest pain

PE – Epidemiology and EtiologyPE – Epidemiology and Etiology

► 100-200,000 deaths per year due to PE100-200,000 deaths per year due to PE► Most PE arise from lower extremity DVTMost PE arise from lower extremity DVT► In patients with DVT, 40-60% will have a PE In patients with DVT, 40-60% will have a PE

on V/Q scanningon V/Q scanning

““Pulmonary embolus is not a disease. It is a Pulmonary embolus is not a disease. It is a complication of DVT.” Ken Moser MDcomplication of DVT.” Ken Moser MD

PE – Clinical PresentationPE – Clinical Presentation

► Dyspnea, pleuritic pain and cough most Dyspnea, pleuritic pain and cough most common symptomscommon symptoms

► Tachypnea, rales and tachycardia most Tachypnea, rales and tachycardia most common signscommon signs

► ABG limited value for diagnosisABG limited value for diagnosis► EKG and CXR often abnormal, but usually EKG and CXR often abnormal, but usually

lacking specificity to aid diagnosislacking specificity to aid diagnosis

PIOPED Study. JAMA. 1990;263(20):2753-59. Stein PD, Goldhaber SZ, Henry JW. Chest 1995;107:139-43

S1Q3T3S1Q3T3

CXR FINDINGSCXR FINDINGS

►Hampton’s Hump:Hampton’s Hump:

-wedge-shaped configuration at -wedge-shaped configuration at lung periphery due to infarcted lunglung periphery due to infarcted lung

Westermark sign:Westermark sign:

-pulmonary oligemia-pulmonary oligemia

PE – Case 2PE – Case 2

► Findings in the ERFindings in the ER Alert white female, mildly anxiousAlert white female, mildly anxious T 101, HR 105, RR 18T 101, HR 105, RR 18 R LE edema and rednessR LE edema and redness Lungs clear to auscultationLungs clear to auscultation ABG – mild respiratory alkalosis; aA gradient = ABG – mild respiratory alkalosis; aA gradient =

1717 CXR showing mild atelectasisCXR showing mild atelectasis

► D-dimer positive as before, troponin normalD-dimer positive as before, troponin normal

PE – Assigning Pretest PE – Assigning Pretest ProbabilityProbability

► Single most important step in the diagnosis Single most important step in the diagnosis of pulmonary embolismof pulmonary embolism

► May be done based on clinical judgment or May be done based on clinical judgment or aided by a clinical scoring systemaided by a clinical scoring system

► Modified Wells Criteria is the most widely Modified Wells Criteria is the most widely used and studiedused and studied

► Reliably stratifies patients by likelihood of PE Reliably stratifies patients by likelihood of PE to allow selection of safe (<2% VTE risk if no to allow selection of safe (<2% VTE risk if no anticoagulation) management strategyanticoagulation) management strategy

PE – Assigning Pretest PE – Assigning Pretest ProbabilityProbability

PE – Use of D-Dimer PE – Use of D-Dimer

► Not helpful when positive, but sensitive Not helpful when positive, but sensitive assay can exclude PE in low risk patientassay can exclude PE in low risk patient

► In patients with moderate pretest probability In patients with moderate pretest probability only rapid quantitative ELISA can only rapid quantitative ELISA can adequately exclude PEadequately exclude PE

► Patients judged to be high risk for PE would Patients judged to be high risk for PE would still have a posttest PE probability of 5-20% still have a posttest PE probability of 5-20% even after negative ELISA and require even after negative ELISA and require further testingfurther testing

Roy PM, Colombet I, Durieux R, et al. Systematic review and meta-analysis of strategies for the diagnosis of suspected pulmonary embolism. BMJ. 2005;331(7511):259

PE – Case 2PE – Case 2

► High risk for PE by Modified Wells Criteria High risk for PE by Modified Wells Criteria

(Wells score = 9)(Wells score = 9)► Positive D-dimer, but negative test would Positive D-dimer, but negative test would

not have safely excluded PEnot have safely excluded PE► Options include:Options include:

CT angiogramCT angiogram V/Q scanV/Q scan Lower extremity compression USLower extremity compression US

PE – Imaging StudiesPE – Imaging Studies

► PIOPED study quantified the value of V/Q PIOPED study quantified the value of V/Q scans in diagnosing PEscans in diagnosing PE Normal/near-normal scans exclude PE in low-Normal/near-normal scans exclude PE in low-

moderate risk patientsmoderate risk patients High probability scans confirm PE in moderate-High probability scans confirm PE in moderate-

high risk patientshigh risk patients Drawbacks: more difficult test and 73% patients Drawbacks: more difficult test and 73% patients

had indeterminate scanshad indeterminate scans► LE compression US showing DVT helps LE compression US showing DVT helps

diagnostically, but a negative study diagnostically, but a negative study insufficient to exclude VTEinsufficient to exclude VTEPIOPED Study. JAMA. 1990;263(20):2753-59

PE – Helical CT (CTA)PE – Helical CT (CTA)

► Eng performed a systematic review (SR) of all Eng performed a systematic review (SR) of all studies & SRs on CTA prior to 2003studies & SRs on CTA prior to 2003 Only 1/6 SRs and 3/8 primary studies found CTA >90% Only 1/6 SRs and 3/8 primary studies found CTA >90%

sensitive for PEsensitive for PE

► In a similar SR in 2005 Roy concludedIn a similar SR in 2005 Roy concluded Negative CTA could safely exclude PE in low risk patientsNegative CTA could safely exclude PE in low risk patients Negative LE US plus negative CTA could exclude PE in Negative LE US plus negative CTA could exclude PE in

moderate risk patientsmoderate risk patients

► At the time of those SRs no studies of faster At the time of those SRs no studies of faster multidetector CTA (MDCT) were availablemultidetector CTA (MDCT) were available

Eng J, Krishnan JA, Segal JB, et al. AJR 2004;183(6):1819-27. Roy PM, Colombet I, Durieux P, et al. BMJ 2005;331(7511):259.

PE – PIOPED IIPE – PIOPED II

► Published June 2006 in NEJMPublished June 2006 in NEJM 1090 consecutive patients with suspected PE1090 consecutive patients with suspected PE All given Modified Wells ScoreAll given Modified Wells Score MDCT - mostly 4 sliceMDCT - mostly 4 slice Gold standard – composite - V/Q, angiogram & LE Gold standard – composite - V/Q, angiogram & LE

USUS► FindingsFindings

MDCT: sens 83% & spec 96% for PEMDCT: sens 83% & spec 96% for PE Positive predictive value >90% in moderate/high Positive predictive value >90% in moderate/high

riskrisk Negative predictive value 96% in low risk patients Negative predictive value 96% in low risk patients

but only 89% in moderate risk patientsbut only 89% in moderate risk patients► Findings generally consistent with Roy’s SRFindings generally consistent with Roy’s SR

Stein PD, Fowler SE, Goodman LR, et al. Multidetector Computed Tomography for Acute Pulmonary Embolism. N Engl J Med 2006;354(22):2317-2327.

PE – Case 2PE – Case 2► MDCT – segmental embolusMDCT – segmental embolus► TherapyTherapy

Enoxaparin 1mg/kg sq every Enoxaparin 1mg/kg sq every 12 hours for 5 days12 hours for 5 days

Warfarin started day 1 at 5 Warfarin started day 1 at 5 mg a daymg a day

CBC on day 3-5 and INR CBC on day 3-5 and INR every day if inpatientevery day if inpatient

May stop enoxaparin after 5 May stop enoxaparin after 5 days if INR > 2.0days if INR > 2.0

Warfarin continued to keep Warfarin continued to keep INR at 2.5 (2.0-3.0 range) for INR at 2.5 (2.0-3.0 range) for 3 months3 months

VTE – Other Therapy IssuesVTE – Other Therapy Issues

► Anticoagulation same for DVT & PEAnticoagulation same for DVT & PE► Thrombolysis - risk/benefit uncertain; clinical Thrombolysis - risk/benefit uncertain; clinical

outcomes generally not improvedoutcomes generally not improved► Vena cava filtersVena cava filters

Contraindication to anticoagulationContraindication to anticoagulation Rarely survivors of massive PERarely survivors of massive PE Rare patients with recurrent VTE on adequate Rare patients with recurrent VTE on adequate

anticoagulationanticoagulation Prophylaxis in certain high risk patientsProphylaxis in certain high risk patients

VTE – Prevention UnderutilizedVTE – Prevention Underutilized

► DVT-FREE DVT-FREE prospective registry prospective registry of 5,451 patients at of 5,451 patients at 183 US hospitals183 US hospitals

► Only 32% of medical Only 32% of medical patients with DVT patients with DVT received DVT received DVT prophylaxisprophylaxis

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US 1991 US 2001 Canada2002

UK 2005Goldhaber S & Tapson V. Am J Cardiol 2004. Slide adapted from Dr. Michael Streiff.

Anderson & Wheeler. Arch Surg 1992. Rahim, et al. Thromb Res 2003. Tapson, et al. Blood 2004

VTE – Prophylaxis in Medical VTE – Prophylaxis in Medical PatientsPatients

► IndicationsIndications CHF or severe respiratory diseaseCHF or severe respiratory disease Bedrest with additional risk factorBedrest with additional risk factor

► CancerCancer► Prior VTEPrior VTE► Acute neurologic diseaseAcute neurologic disease► Inflammatory bowel diseaseInflammatory bowel disease

Most ICU patientsMost ICU patients

► OptionsOptions Low dose unfractionated heparin or LMWHLow dose unfractionated heparin or LMWH Sequential compression devicesSequential compression devices Graduated compression stockingsGraduated compression stockings

Take Home PointsTake Home Points

► DVT and PE are the same diseaseDVT and PE are the same disease► Assigning pretest probability for VTE is an essential Assigning pretest probability for VTE is an essential

step in diagnosisstep in diagnosis► DVT & PE can diagnosed or excluded in many but DVT & PE can diagnosed or excluded in many but

not all patients using noninvasive meansnot all patients using noninvasive means► VTE for can be safely managed with heparin for at VTE for can be safely managed with heparin for at

least 5 days and simultaneous warfarin without a least 5 days and simultaneous warfarin without a loading doseloading dose

► Always consider VTE prophylaxis in inpatientsAlways consider VTE prophylaxis in inpatients