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Venous Thromboembolism. Justin A. Glass, MD Emory Family Medicine 7.3.08. Objectives. Clinical review of VTE History Prevalence Diagnosis Treatment Prevention . Venous Thromboembolism: DVT. Venous Thromboembolism : PE.

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venous thromboembolism

Venous Thromboembolism

Justin A. Glass, MD

Emory Family Medicine

7.3.08

objectives
Objectives
  • Clinical review of VTE
    • History
    • Prevalence
    • Diagnosis
    • Treatment
    • Prevention
venous thromboembolism pe
Venous Thromboembolism: PE
  • An autopsy on Derrick Thomas this morning showed that the nine-time Pro Bowl linebacker died of a blood clot in an artery between his heart and lungs.
  • Dr. Barth Green -- the neurosurgeon who along with Dr. Frank Eismont had operated on Thomas on Jan. 24 for a spinal cord injury that had left him paralyzed from the chest down – said “It was what is called a saddle embolus”

NY Times, 2/10/2000

vte prevalence
VTE Prevalence
  • 600,000 VTE’s in U.S. in 1991 (0.2% of the population)
  • Incidence is increasing
  • Why do we care?
    • 50% of untreated DVT’s will be complicated by a PE
    • 26% of unrecognized pulmonary embolisms are eventually fatal
    • 16% of all hospital deaths due to PE
  • The Worcester DVT Study. Arch Intern Med. 1991;151:933-938.
vte pathogenesis
VTE: Pathogenesis
  • Virchow’s Triad
    • Venous stasis
    • Endothelial injury
    • Hypercoagulability

Brotman DJ, Deitcher SR, Lip GY, Matzdorff AC. Virchow's triad revisited. South Med J. 2004;97:213-214.

vte risks
VTE Risks
  • Increasing age
  • Cancer
  • Pregnancy
    • 60/100,000 women
  • Immobility
  • Surgery
  • Hormone replacement therapy / OCP’s
    • 10-30 / 100,000 users vs 4-8/100,000 non-users
  • Thrombophilic disorders
maria
Maria
  • 38 yr old female presents with pain and mild swelling in L LE. Pt was hiking recently when she slipped, fell and injured R knee. Her knee immediately swelled. She felt unstable w/ walking due to pain and sought care at a local ER. A knee immobilizer was placed. She followed up with an orthopedic doctor who diagnosed an acute ACL rupture. An MRI confirmed this and she underwent allograph repair 3 weeks ago. She is currently doing rehab with a PT.
maria cont
Maria (cont)
  • PMH: Negative
  • PSH: ACL repair (6/12/08)
  • Meds: Ibuprofen prn / Vicodin prn / Ortho Tricyclen
  • Allergies: NKDA
  • Soc Hx: Scrub tech at EUH No Tob / Rare Etoh
maria on exam
Maria on exam
  • Vitals: T 97.2 P 90 BP 110/70 R 14
  • Pulm: CTA
  • CV: Regular
  • Ext: Moderate swelling about R knee w/ healing incision. 1+ pitting edema L LE. Mild pain with squeezing calf on L leg. None on R leg. Negative Homan’s sign. Calf circumference is 1 cm larger L than R.
dvt physical exam
DVT - Physical Exam

Calf tenderness

Homan’s Sign

Differential Swelling

www.netterimages.com

diagnosis
Diagnosis
  • Well’s Criteria (DVT)
    • Active cancer (tx within <6 mos or palliative care) (1)
    • Calf swelling (3 cm difference – 10 cm below tib tub) (1)
    • Collateral superficial veins (1)
    • Paralysis, paresis, or recent immobilization LE (1)
    • Pitting edema confined to involved leg (1)
    • Bedridden within 3 days or surgery w/ anes <12 wks (1)
    • Swollen leg (1)
    • Alternate diagnosis more likely (-2)

Probability: Low (0 pts) Intermediate (1-2) High (3)

Lancet 2002;350:1796.

d dimer
D-Dimer
  • Clinical utility in VTE diagnosis?
d dimer16
D-Dimer
  • If D-Dimer is measured by ELISA or immunoturbidimetric method, it is highly sensitive for active VTE.
    • Most studies use cutoff <500 ng/mL
    • Sensitivity 96-100%
  • If D-Dimer is measured by semiquantitative latex agglutination, it is not highly sensitive.
d dimer17
D-Dimer
  • A low clinical probability by Well’s Criteria plus a normal D-Dimer implies a LOW clinical risk of VTE.
    • 0.5% of patients develop DVT in 3 months
  • Further testing can be deferred in this patient population.

Fancher TL, White RH, Kravitz RL. Combined use of rapid D-dimer testing and estimation of clinical probability in the diagnosis of DVT: systematic review. BMJ. 2004;329:821

Ann Fam Med 2007;5:57-62.

d dimer18
D-Dimer
  • What is the risk of DVT in a patient with a normal D-Dimer and a moderate or high risk Well’s score?
  • Moderate: 3.5%
  • High risk: 21%

Fancher TL, White RH, Kravitz RL. Combined use of rapid D-dimer testing and estimation of clinical probability in the diagnosis of DVT: systematic review. BMJ. 2004;329:821.

vte diagnosis ultrasonography
VTE Diagnosis: Ultrasonography
  • Duplex scan of LE
    • Compressibility of the vein
    • Doppler flow within the vein
  • Symptomatic patient with proximal LE DVT
    • Sensitivity: 89-96%
    • Specificity: 94-99%
vte diagnosis ultrasonography20
VTE Diagnosis: Ultrasonography
  • Asymptomatic patient with proximal LE DVT
    • Sensitivity: 47-62%
  • Symptomatic patient with distal LE DVT
    • Sensitivity: 73-93%
vte diagnosis venography
VTE Diagnosis: Venography
  • Gold standard for DVT
  • Primarily a research tool now
albert
Albert
  • 62 yr old male presents to the ER with complaint of pleuritic CP. Present x 1 day. No injury. Feels SOB with walking. No fever. No cough. No LE pain.
  • PMH: Colon CA s/p L colectomy 4/08 / HTN / BPH
  • Meds: Lisinopril / Tamsulosin / ASA / MVI
  • NKDA
  • Soc Hx: No Tob / No Etoh
albert24
Albert
  • Physical
    • T 99.1 P 110 BP 135/85 R 22 O2 sat 95% RA
    • Pulm: CTA good AF
    • CV: Regular No murmurs
    • Ext: No edema. Negative Homan’s sign
albert25
Albert
  • What is the likelihood of a PE?
diagnosis of pe common findings
Diagnosis of PE: Common findings
  • History
    • Dyspnea (73%)
    • Pleuritic Chest pain (66%)
    • Cough (37%)
    • Hemoptysis (13%)
  • Physical
    • Tachypnea (70%)
    • Rales (51%)
    • Tachycardia (30%)

Stein, PD, et al. Chest 1991 Sep;100(3):598-603.

Stein, PD, et al. Am J Cardiol 1991; 68:1723-

diagnosis27
Diagnosis
  • Well’s Criteria (PE)
    • Cancer (1)
    • Hemoptysis (1)
    • Heart rate more than 100 (1.5)
    • Previous episode of VTE (1.5)
    • Recent surgery or immobilization (1.5)
    • Alternate diagnosis less likely than PE (3)
    • Clinical signs of DVT (3)

Probability: Low (0-1) Intermediate (2-6) High (7+)

Am J Med 2002;113:270.

diagnosis of pe common findings28
Diagnosis of PE: Common findings
  • D-Dimer elevation
    • >500 ng/ml
  • A-a gradient >20 mm Hg
    • (713(FIO2) – PaCO2/0.8) – PaO2
  • BNP or proBNP elevation
    • Sensitivity and Specificity are approx 60%
  • Troponin elevation
    • 30-50% of mod/large PE’s have troponin elevation
pe definitive testing
PE: Definitive Testing
  • What test should be ordered?
pe definitive testing33
PE: Definitive Testing
  • VQ Scan
  • Spiral CT Chest
  • Pulmonary angiography
vq scan
VQ Scan

www.imagingpathways.health.wa.gov.au/.../vq.jpg

vq scanning
VQ Scanning
  • Nuclear medicine scan to detect perfusion-ventilation mismatch.
    • Indeterminate
    • Normal
    • Low probability
    • Intermediate probability
    • High probability
likelihood of pe based on vq result
Likelihood of PE based on VQ Result

Clinical Probability of PE

VQ Scan Result High Intermediate Low

High 95 86 56

Intermediate 66 28 15

Low 40 15 4

Normal 0 6 2

Value of the VQ scan in acute pulmonary embolism. Results of the prospective investigation of pulmonary embolism diagnosis (PIOPED). The PIOPED Investigators. JAMA 1990 May 23-30;263(20):2753-9.

diagnosis of vte spiral ct chest
Diagnosis of VTE: Spiral CT Chest
  • Detection of pulmonary embolism by timed application of contrast to the pulmonary vasculature
    • Heterogenity in results across trials.
      • Sensitivity: 40-100% (PIOPED 2: 83%)
      • Specificity: 78-100% (PIOPED 2: 96%)

Segal J, Eng J, Tamariz L, Bass E. Review of the evidence on diagnosis of deep venous thrombosis and pulmonary embolism. Ann Fam Med. 2007;5:63-73.

spiral ct
Spiral CT

www.imagingpathways.health.wa.gov.au/.../vq.jpg

diagnosis of vte spiral ct chest40
Diagnosis of VTE: Spiral CT Chest
  • PIOPED 2 Study

Clinical Probability of PE

CT ResultLowIntermediateHigh

Positive for PE 58% 92% 98%

Negative for PE 4% 11% 40%

Table show % with PE by “composite reference standard”

N Engl J Med 2006;354:2317-27.

diagnosis of vte spiral ct chest41
Diagnosis of VTE: Spiral CT Chest
  • PIOPED 2 Study

Clinical Probability of PE

CT ResultLowIntermediateHigh

Positive for PE 58% 92% 98%

Negative for PE 4% 11%40%

Table show % with PE by “composite reference standard”

N Engl J Med 2006;354:2317-27.

pe diagnosis
PE Diagnosis
  • VQ scanning versus Spiral CT Chest
    • Randomized trial of patients suspected of having PE, n=1471

False Negative Rate

Spiral CT 0.6%

VQ Scan 1.0%

vte diagnosis
VTE Diagnosis
  • What should you do if you have a patient with a high probability Well’s score for PE and a negative spiral CT Chest?
    • Single or sequential duplex scan of the LE OR
    • Pulmonary angiography
pe diagnosis44
PE Diagnosis
  • Christopher Study (n=3306)
    • Well’s score obtained. Two cohorts defined
      • Well’s 4 or less (PE unlikely)
      • Well’s >4 (PE likely)
    • D-Dimer obtained if Well’s 4 or less
    • If Well’s 4 or less and D-Dimer negative, conclude - no PE
    • If Well’s 4 or less and D-Dimer positive, obtain Spiral CT
    • If Well’s >4, obtain Spiral CT

JAMA. 2006;295:172-179

pe diagnosis45
PE Diagnosis

Christopher Study (cont)

Initial WorkupFollow-up: 3 months

Low Risk Well’s / Negative D-Dimer 0.5% with PE

No Spiral CT done

Negative Spiral CT 1.3% with PE

Positive Spiral CT initially 3.0% with PE

treatment of dvt
Treatment of DVT
  • Low Molecular Weight Heparin (LMWH)
    • 1 mg/kg q 12 hrs or 1.5 mg/kg q 24 hrs
  • Coumadin x 3 months (Goal INR 2-3)
    • LMWH should be overlapped until both of the following conditions are met:
      • INR >2 x days
      • At least five days of LMWH given
  • Pressure stockings
treatment of pe
Treatment of PE
  • Refer to DVT guidelines, with addition of:
    • Unfractionated heparin is considered equal option to LMWH.
    • Heparin dosing should be adjusted to achieve aPTT 1.5-2.5 x the upper limit of normal.
    • Strict guidelines need to be in place to prevent undercoagulation or overcoagulation
unfractionated heparin
Unfractionated heparin
  • Weight based nomogram

1. Bolus 80 units/kg then continuous infusion at 18 units/kg.

2. Check aPTT 6 hrs

aPTT <35 (<1.2 x control): Bolus 80 units/kg and increase

infusion by 4 units/kg

aPTT 35-45 (1.2 – 1.5 x control): Bolus 40 units/kg then increase by 2

units/kg/hr

aPTT 46-70 (1.5-2.3 x control): No change

aPTT 71-90 (2.3 – 3.0 x control): Decrease infusion by 2 units/kg/hr

aPTT 90+ (>3.0 x control): Hold infusion x 1 hour, then decrease

infusion by 3 units/kg/hr

3. Return to step #2 if dose change.

4. If no dose change, check aPTT q 24 hrs

unfractioned heparin vs lmwh
Unfractioned Heparin vs LMWH
  • Meta-analyses have shown:
    • Lower recurrence DVT (2.7% vs 7.0%)
    • Lower incidence major bleeding (0.9% vs 3.2%)
    • Lower death rate at 3 months (OR 0.71 (0.53-0.94))

(All favoring LMWH)

Am J Med 1996 Mar;100(3):269-77

Ann Intern Med 1999 May 18;130(10):800-9

vte in pregnancy
VTE in Pregnancy
  • Incidence: 0.5 -1 case / 1000 pregnancies
  • Relative risk (RR) = 5.0
  • Factors
    • Postpartum
    • C-section
vte in pregnancy52
VTE in Pregnancy
  • Treatment
    • LMWH
      • Need to monitor anti-factor Xa levels q 4 weeks (4 hrs after dose)
      • Goal: 0.6 – 1.0 IU/ml (bid dosing) or 1 -2 IU/ml for q day dosing
    • Heparin bridge
      • Stop LMWH 2 weeks before delivery. (no epidural within 24 hrs LWMW)
      • Start Unfractionated Heparin with goal PTT 1.5-2.3 normal
      • Hold for delivery with restart 6 hours after vaginal delivery or 12 hours after C-section
    • Coumadin in the post-partum period
vte in pregnancy53
VTE in Pregnancy
  • Coumadin is teratogenic
    • Nasal hypoplasia
    • Limb hypoplasia
    • Optic disc atrophy
    • Neurodevelopmental delays
    • However, ok with nursing.
vte in pregnancy54
VTE in Pregnancy
  • Duration of therapy
    • Three to Six months
    • Need to cover at least six weeks post-partum
vte in chronic kidney disease
VTE in Chronic Kidney Disease
  • No consensus guidelines exist for choice of anticoagulation in patients with GFR < 30 ml/min
  • Bleeding risk and recurrent VTE risk are higher in such patients
  • If using LMWH, consider monitoring anti-factor Xa levels.
vte in patient with malignancy
VTE In Patient With Malignancy
  • LMWH favored over coumadin for longterm therapy
    • CLOT Trial (Randomized trial,n=672)
      • Recurrent DVT 8% (dalteparin) vs 16% (warfarin)
      • No difference in major bleeding, death
    • Dosing: Dalteparin (Fragmin) 200 IU/kg q day x 1 month, then 150 IU/kg q day x 5 months.
    • Max dose: 18,000 IU/day
    • No monitoring required.
vte in obese pt
VTE in Obese Pt
  • LMWH needs to be dose adjusted as follows:
    • Enoxaparin – Drop dose by 25% for patients >144 kg
    • Dalteparin – Drop dose by 25% for patients > 190 kg
workup for thrombophilia
Workup for thrombophilia
  • No clear guideline on when to screen for inherited thrombophilic state. Consider in idiopathic VTE or recurrent VTE.
  • Probably a factor in up to 30% of VTE’s
workup for thrombophilia60
Workup for Thrombophilia
  • 1st group (genetic tests)
    • Prothrombin 20210A
    • Factor V Leiden (cheaper to look for APC resistance)
  • 2nd group (At least two weeks after anticoagulation course completed)
    • Protein C activity
    • Protein S activity
    • Antithrombin activity
    • APC resistance (low value can indicate Factor V Leiden)
    • AntiphospholidAb’s
adverse effects of heparinoids
Adverse Effects of Heparinoids
  • Bleeding
  • HIT
  • Respiratory collapse
adverse effects
Adverse Effects
  • Bleeding
    • If severe, use protamine (1 mg per 100 units LWMH or Heparin)
hit heparin induced thrombocytopenia
HIT (Heparin Induced Thrombocytopenia)
  • Uncommon complication of heparinoid therapy
    • Occurs 4-10 days after heparin started (Type 2)
    • Incidence: Unfrac Heparin (2.6%) -- LMWH (0.2%)
  • Diagnosis
    • Thrombocytopenia in appropriate time interval
    • Skin necrosis can occur
    • HIT assay
  • Treatment
    • Stop Heparin
    • Start lepirudin (direct thrombin inhibitor)
    • 0.1 to 0.4 mg/kg bolus followed by 0.1 to 0.15 mg/kg per hour infusion

Blood 2005 Oct 15;106(8):2710-5. Epub 2005 Jun 28

heparin induced anaphylaxis
Heparin induced anaphylaxis
  • Case reports in 2008.
  • Hypotension / allergic reactions / deaths
  • Linked epidemiologically to unfractionated heparin used mainly at dialysis centers
  • Batches contaminated with oversulfated condroitin sulfate (OSCS)
  • Potent activator of the contact system -- leading to kinins and C5a.
additional references
Additional References
  • Current Diagnosis of VTE in Primary Care: A Clinical Practice Guideline from the AAFP and the ACP. Ann Fam Med 2007;5:57-62.
  • Management of VTE: A Clinical Practice Guideline from the AAFP and the ACP. Ann Intern Med. 2007;146:204-210.