1. Venous Thromboembolism: Deep Venous Thrombosis and Pulmonary Embolism
2006 Capital Conference
Andrews Air Force Base
CDR Kenneth S. Yew MC, USN
Uniformed Services University
Edited by Paul Saleeb

2. Objectives
Recognize common presentations of deep venous thrombosis (DVT) and pulmonary embolus (PE)
Understand evidence-based diagnostic and therapeutic strategies for DVT/PE
Understand the role of prevention for DVT/PE and use of prevention strategies

3. Case 1
37 yo moderately obese female on OCP presents to your office with a two day history of painless R leg swelling. She’s been elevating her leg several days after a severe ankle sprain during a mother-daughter soccer game.
No prior medical history, recent surgery or weight loss. She is a non-smoker and drinks rarely.
Exam is notable for R ankle splint and pitting edema in R calf, which is 1.5 cm larger than the L.

4. DVT – Epidemiology and Etiology
Annual incidence of venous thromboembolism (VTE) is 1/1000
DVT accounts for one half of VTE
Carefully evaluated, up to 80% of patients with VTE have one or more risk factors
Majority of lower extremity DVT arise from calf veins but ~20% begin in proximal veins
About 20% of calf-limited DVTs will propagate proximally

5. DVT – VTE Risk Factors Malignancy Surgery Trauma Pregnancy
Oral contraceptives or hormonal therapy
Immobilization
Inherited thrombophillia
Presence of venous catheter
Congestive failure
Antiphospholipid antibody syndrome
Hyperviscosity
Nephrotic syndrome
Inflammatory bowel disease
In addition a study in a Nurses Health study cohort noted obesity, smoking and HTN as risk factors for PE in women.

6. DVT – Clinical Presentation
Classically = calf pain, tenderness, swelling, redness and Homan’s sign
Overall sens/spec = 3-91%
Unreliable for diagnostic decisions
Wells developed and tested a clinical 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):

7. DVT – Wells Score Cancer Paralysis or plaster immobilization
The following were assigned a point value of 1 if present:
Cancer
Paralysis or plaster immobilization
Bedrest > 3d or surgery in past 4 wks
Localized tenderness
Entire leg swollen
Calf > 3cm larger than unaffected leg
Pitting edema greater than unaffected leg
Collateral superficial veins
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

8. DVT – Case 1
Our patient has 2-3 risk factors (OCP, +/- immobilization and trauma
Her Wells score gives her a moderate pretest probability for DVT
A d-dimer test is performed…

9. DVT – D-Dimer Fibrin degradation product elevated in active thrombosis
Negative test can help exclude VTE
Preferred test
Quantitative Rapid ELISA – sensitivity 96/95% for DVT/PE
Other methods include latex agglutination and RBC agglutination (SimpliRED)
Less helpful in malignancy and recent surgery.
Rapid RBC agglutination (SimpliRED) – sensitivity 87/78% for DVT/PE
1st generation ELISA accurate but slow
Latex agglutination only useful if quantitative
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):

10. DVT – D-Dimer
In 283 patients with suspected DVT, low-moderate Wells DVT score and negative d-dimer only 1 (NPV 99.6%) had DVT over next 3 months
556 consecutive patients with suspected DVT, 283 (51%) had low-mod prob and neg d-dimer
Used a quantitative latex agglutination test (sens 97.1% in this study; method sens 85%/89% for DVT/PE in Stien SR)
Sensitive d-dimer testing can rule out DVT in low-moderate risk patients
Bates SM, Kearon C, Crowther M, et al. Ann Intern Med. 2003;138:787-94

11. DVT – Case 1 Our patient has a positive quantitative ELISA
Unfortunately a positive d-dimer is not helpful diagnostically
An imaging study is done…

12. DVT – Imaging Compression US – first line test, high sens/spec
Available imaging and ancillary tests:
Compression US – first line test, high sens/spec
Venography – gold standard
MRI – Lower quality evidence only at present
Impedance plesmythography – not in US
Complete lower extremity US – experimental
Compression US with doppler or duplex – good for symptomatic proximal DVT, only 70% sens for calf-limited DVT.
Venography less common due to time, difficulty, invasiveness, but still best for recurrences, high prob patients with neg or incomplete US or eval for calf-limited DVT.
MRI – may have limited availability, more expensive. Available studies examining accuracy of this method not same quality as for US and venography, but have suggested high sens/spec for DVT.
Complete LE US, has been studied in a couple of centers with low rates of subsequent VTE events after a single negative study. Technically demanding and may not catch on.

13. DVT – Case 1 Compression US negative Options include:
Venography or MRI
Serial compression US – single US done at 5-7 days reliably excludes calf-limited DVT
Follow clinically for resolution of symptoms – riskier, no data supporting safety 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

14. 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.

15. Case 2
The patient in Case 1 elected to be followed clinically. She returned to clinic 3 days later with persistent swelling, but no new symptoms
She was to return the following week, but instead you are called to the ER 10 days later after she presents with acute onset of dyspnea and pleuritic chest pain

16. PE – Epidemiology and Etiology
,000 deaths per year due to PE
Most PE arise from lower extremity DVT
In patients with DVT, 40-60% will have a PE on V/Q scanning
“Pulmonary embolus is not a disease. It is a complication of DVT.” Ken Moser MD

17. PE – Clinical Presentation
Dyspnea, pleuritic pain and cough most common symptoms
Tachypnea, rales and tachycardia most common signs
ABG limited value for diagnosis
EKG and CXR often abnormal, but usually lacking specificity to aid diagnosis
Pneumonia/pleurisy syndrome – 65%
Unexplained dyspnea syndrome – 22%
Central catastrophic syndrome – 8%
Chronic pulmonary hypertension syndrome
Pulmonary sepsis syndrome – T<102 in 14%
† Percentages specified are from those observed in the PIOPED study.
AA gradient normal in 8-23% of patients with angiographically proven PE.
PIOPED Study. JAMA. 1990;263(20): Stein PD, Goldhaber SZ, Henry JW. Chest 1995;107:139-43

19. S1Q3T3

20. CXR FINDINGS Hampton’s Hump:
-wedge-shaped configuration at lung periphery due to infarcted lung
Westermark sign:
-pulmonary oligemia

23. PE – Case 2 Findings in the ER
Alert white female, mildly anxious
T 101, HR 105, RR 18
R LE edema and redness
Lungs clear to auscultation
ABG – mild respiratory alkalosis; aA gradient = 17
CXR showing mild atelectasis
D-dimer positive as before, troponin normal

24. PE – Assigning Pretest Probability
Single most important step in the diagnosis of pulmonary embolism
May be done based on clinical judgment or aided by a clinical scoring system
Modified Wells Criteria is the most widely used and studied
Reliably stratifies patients by likelihood of PE to allow selection of safe (<2% VTE risk if no anticoagulation) management strategy
Low(57%) 1.3%; Moderate(36%) 16.2% and High(7%) 37.5%

25. PE – Assigning Pretest Probability

26. PE – Use of D-Dimer
Not helpful when positive, but sensitive assay can exclude PE in low risk patient
In patients with moderate pretest probability only rapid quantitative ELISA can adequately exclude PE
Patients judged to be high risk for PE would still have a posttest PE probability of 5-20% even after negative ELISA and require further 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

27. PE – Case 2 High risk for PE by Modified Wells Criteria
(Wells score = 9)
Positive D-dimer, but negative test would not have safely excluded PE
Options include:
CT angiogram
V/Q scan
Lower extremity compression US

28. PE – Imaging Studies
PIOPED study quantified the value of V/Q scans in diagnosing PE
Normal/near-normal scans exclude PE in low-moderate risk patients
High probability scans confirm PE in moderate-high risk patients
Drawbacks: more difficult test and 73% patients had indeterminate scans
LE compression US showing DVT helps diagnostically, but a negative study insufficient to exclude VTE
PIOPED Study. JAMA. 1990;263(20):

30. PE – Helical CT (CTA)
Eng performed a systematic review (SR) of all studies & SRs on CTA prior to 2003
Only 1/6 SRs and 3/8 primary studies found CTA >90% sensitive for PE
In a similar SR in 2005 Roy concluded
Negative CTA could safely exclude PE in low risk patients
Negative LE US plus negative CTA could exclude PE in moderate risk patients
At the time of those SRs no studies of faster multidetector CTA (MDCT) were available
Faster scanning times and 50% thinner cuts presumably would result in increased sensitivity for smaller PEs
Eng J, Krishnan JA, Segal JB, et al. AJR 2004;183(6): Roy PM, Colombet I, Durieux P, et al. BMJ 2005;331(7511):259.

31. PE – PIOPED II Published June 2006 in NEJM Findings
1090 consecutive patients with suspected PE
All given Modified Wells Score
MDCT - mostly 4 slice
Gold standard – composite - V/Q, angiogram & LE US
Findings
MDCT: sens 83% & spec 96% for PE
Positive predictive value >90% in moderate/high risk
Negative predictive value 96% in low risk patients but only 89% in moderate risk patients
Findings generally consistent with Roy’s SR
Concordant findings helpful -
Need neg LE US to exclude in moderate risk patients
Discordant findings – low pretest – pos CT or high pretest – neg CT need more testing.
Stein PD, Fowler SE, Goodman LR, et al. Multidetector Computed Tomography for Acute Pulmonary Embolism. N Engl J Med 2006;354(22):

32. PE – Case 2 MDCT – segmental embolus Therapy
Enoxaparin 1mg/kg sq every 12 hours for 5 days
Warfarin started day 1 at 5 mg a day
CBC on day 3-5 and INR every day if inpatient
May stop enoxaparin after 5 days if INR > 2.0
Warfarin continued to keep INR at 2.5 ( range) for 3 months
Heparin also an option but since outcome if tied to the rapidity of adequate anticoagulation, LMWH preferred due to its easier dosing. Check q2d CBC if using heparin.
NO reason to delay warfarin. NO reason to load warfarin – only leads to higher rate of high INRs and bleeding complications. Must continue heparin or LMWH at least 5 days and ensure INR>2.0 prior to discontinuing.

33. VTE – Other Therapy Issues
Anticoagulation same for DVT & PE
Thrombolysis - risk/benefit uncertain; clinical outcomes generally not improved
Vena cava filters
Contraindication to anticoagulation
Rarely survivors of massive PE
Rare patients with recurrent VTE on adequate anticoagulation
Prophylaxis in certain high risk patients
PE – faster clot resolution in short term, but no documented improvement in mortality or symptom resolution
DVT – possible isolated indication in massive VTE. NO reduction in postphlebitic syndrome.
Contraindication to anicoagulation – recent surgery, CVA or active bleeding
High risk patients for filter – cor pulmonale, prior VTE diagnosed with hip fx or cancer

34. VTE – Prevention Underutilized
DVT-FREE prospective registry of 5,451 patients at 183 US hospitals
Only 32% of medical patients with DVT received DVT prophylaxis
Goldhaber S & Tapson V. Am J Cardiol Slide adapted from Dr. Michael Streiff.
Anderson & Wheeler. Arch Surg Rahim, et al. Thromb Res Tapson, et al. Blood 2004

35. VTE – Prophylaxis in Medical Patients
Indications
CHF or severe respiratory disease
Bedrest with additional risk factor
Cancer
Prior VTE
Acute neurologic disease
Inflammatory bowel disease
Most ICU patients
Options
Low dose unfractionated heparin or LMWH
Sequential compression devices
Graduated compression stockings

36. Take Home Points DVT and PE are the same disease
Assigning pretest probability for VTE is an essential step in diagnosis
DVT & PE can diagnosed or excluded in many but not all patients using noninvasive means
VTE for can be safely managed with heparin for at least 5 days and simultaneous warfarin without a loading dose
Always consider VTE prophylaxis in inpatients