Brian M. Johnson, MD CCRMC PBL 11/7/12 Deep Vein Thrombosis Brian M. Johnson, MD CCRMC PBL 11/7/12

Case 1 Mrs. Z, a 44-year-old woman without significant PMH, presents for an urgent visit with left leg swelling of two days duration. She takes no medications and reports moderate leg pain but no chest pain, shortness of breath, or palpitations.

What is the differential diagnosis of unilateral leg swelling? DVT 2. Cellulitis 3. Baker’s cyst 4. Lymphedema 5. Fracture Post-thrombotic syndrome Venous insufficiency Scorpions? Or bee stings? Toxins Mass Trauma / Compartment syndrome

What are risk factors for DVT? Hospitalization Long-term immobility OCP Smoking Age Surgery Cancer CHF Renal disease Cirrhosis Pregnancy Anti-psychotics Thrombophilias Obesity Restrictive clothing Gender Lupus (and other autoimmune diseases) Sickle Cell

Case Continued… She reports that she has no family history of blood clots to her knowledge and that she is not pregnant. She denies any “warning signs” of cancer and is up to date on her cancer screening (mammogram, Pap smear; no colorectal cancer screening, but she denies family history of colorectal cancer so she is not yet due). She denies recent immobilization or trauma. Her exam is significant for a minimally swollen right calf. To ensure a reliable assessment of circumference, you mark off 10cm below each tibial tuberosity and measure the circumference at that level. You find that the right calf measures 1cm larger in circumference than the left. There is no edema or skin changes; no masses/cords are palpable. The thighs are symmetric, and no superficial veins are noted.

How could you determine the probability of the DVT in this patient?

What is the probability that this patient has a DVT? Modified Wells Clinical feature Score* Active cancer within 6 mo 1 Paralysis, paresis, or cast of lower extremity Recently bedridden >3 d or major surgery within 4 wk Localized tenderness along distribution of deep vein system Calf diameter >3 cm larger than opposite leg† Pitting edema Collateral superficial veins (nonvaricose) Alternative diagnosis as likely or greater than that of DVT Clinical model for predicting pretest probability for DVT *Interpretation: 0 = low probability = 3% frequency of DVT; 1-2 = medium probability= 17% frequency of DVT; ≥3 = high probability = 75% frequency of DVT. †Measured 10 cm below tibial tuberosity. -2

How would a d-dimer help? Statistically Sensitive not Specific (useful if it’s negative) High false positive rate Biomedically measures level of coagulation process in the body

Case 2 Ms. W, comes with the exact same presenting complaint and past medical history. The only difference in the presentation of Ms. W. is that she does report that she had the “flu” about one week ago and was in bed for four to five days. Additionally, her exam is significant for a swollen and tender right calf, measuring 4 cm wider in circumference than the left. There is pitting edema on the right lower extremity, extending to the inferior calf. There is no change in the skin, and no masses/cords are palpable. The thighs are symmetric, and no superficial veins are noted.

What’s the probability this patient has a DVT? 75%!! High, with wells score greater than 3

What’s the value of doing a d-dimer? If high probability 21% still positive for DVT even with negative D-dimer

What other test could you preform? Venous Doppler (venography)

Remember: the superficial femoral vein is a deep vein

Operating characteristics of diagnostic tests for proximal DVT Operating characteristics of diagnostic tests for proximal DVT* Black et al. * Diagnostic test Sensitivity, % Specificity, % Positive LR Negative LR Venography ~100 Infinity Duplex ultrasonography 95 19 0.05 Impedence plethysmography 80 16 0.21 Iodine 125 fibrinogen scan 79 62 2.1 0.34 D-Dimer level 88-100 55-80 1.9-5.0 0.4-0.02 LR = likelihood ratio.

U/S negative. End of story? With high probability clinical exam but NEGATIVE U/S: Consider other imaging, repeat study or obtain D-dimer. Consider treatment

U/S positive. Can she be treated as an outpatient? Yes Need immediate anticoagulation (i.e. Lovenox) then can bridge to warfarin No Obesity Cachetic Renal failure (GFR <40) High bleeding risk Complicated medical history Poor resources

For how long? Unprovoked 6 months? Provoked 6 months?

What’s a provoked DVT and why does it matter? Risk factors Major: Cancer, Major Surgery, Major trauma Minor: Preg., long flight, OCP, smoking, minor trauma, minor surgery

Risk of VTE recurrence after stopping anticoagulation Risk factor 1st year Next 5 years Distal DVT 3% <10% Major transient 10% Minor transient 5-6% 15% Unprovoked At least 10% 30% Recurrent >10% >30% This is why duration of therapy is based on provoked vs. unprovoked Kearon, American Society Hematology Dec. 2004

Is longer anticoagulation better in idiopathic DVT? TRIAL Duration Recurrence THRIVE 3mo 7.6/ 100pt yrs 2.1 yrs 2.6/100pt yrs PREVENT 6mo 12.6% 18 mo 2.8% PREVENT: Idiopathic DVT THRIVE Schulman et al. N Engl J Med 2003 Ridker et al. N Engl J Med. 2003

Do the experts agree with the ACCP recommendations? 8th ACCP guideline British Thoracic Society Recent recommendations First VTE, Provoked 3 months 4-6 weeks 3 months if distal or upper extremity; 6 if proximal DVT or PE Idiopathic At least 3 months, evaluate for indefinite tx Indefinite Samuel Z. Goldhaber

Should I do the thrombophilia work up?

Incidence of recurrent VTE Christensen et al. JAMA 2005. Patient group (total 474 pt) Recurrence of VTE/year With 1 thrombophilia 2.5% Initial VTE provoked 1.8% Initial VTE idiopathic 3.3% Idiopathic with thrombophilia 3.4% Idiopathic without thrombophilia 3.2% Total group 2.6% So basically having a thombophilia is much less predictive of recurrence than having an idiopathic VTE. But this is a small study that didn’t separate out the thrombophilias individually. Later they do comment that APLA does increase risk of recurrence. Based on this data, both the author of the above study and the author of a recent article in the american journal of medicine (2008) suggests that thrombophilia work up is almost never useful after a first event. They do recommend testing for APLA as it does have a significant impact on risk of recurrence.

How can I determine who’s at risk for recurrent clot? Thrombophilia Male gender Active cancer (i.e. ongoing risk factors) Recurrent dvt Proximal over distal Morbidity from DVT Repeat studies (US and ddimer)

Algorithm for Determining Duration of Treatment After 3m CHECK U/S assess bleeding risk (& discuss indefinite tx if pt with PE, Male or thrombophilia) Female: No residual clot. Clinical risk rule <1, stop AC Male: No residual clot, stop AC, measure d-dimer after 30d and stop if normal. Evidence of residual clot, continue AC and repeat U/S

REFERENCES Bates SM, Kearon C, Crowther M, et al. A diagnostic strategy involving a quantitative latex D-dimer assay reliably excludes deep venous thrombosis. Annals of Internal Medicine. 2003;138(10):787-794. Black ER, Bordley DR, Tape TG, Panzer RJ. Diagnostic Strategies for Common Medical Problems. Philadelphia: American College of Physicians; 1999. Bruinstoop, E., Klok, F. A.,Van de Ree, M. A., Oosterwijk, F. L. and Huisman, M. V., Elevated d-dimer levels predict recurrence in patients with idiopathic venous thromboembolism: a meta-analysis. Journal of Thrombosis and Haemostasis, 2009;7: 611–618 Ofri D Diagnosis and treatment of deep vein thrombosis West J Med. 2000 September; 173(3): 194–197. Ridker PM, Goldhaber SZ, Danielson E, Rosenberg Y, Eby CS, Deitcher SR, Cushman M, Moll S, Kessler CM, Elliott CG, Paulson R, Wong T, Bauer KA, Schwartz BA, Miletich JP, Bounameaux H, Glynn RJ, PREVENT Investigators N Engl J Med. 2003;348(15):1425 Rodger et al. Identifying unprovoked thromboembolism patients at low risk for recurrence who can discontinue anticoagulant therapy. CMAJ August 26, 2008 vol. 179 no. 5 Schulman S, Wåhlander K, Lundström T, Clason SB, Eriksson H. Secondary prevention of venous thromboembolism with the oral direct thrombin inhibitor ximelagatran.. N Engl J Med 2003 Oct 30;349:1713-21