Deep Vein Thrombosis Therapy

Deep Vein Thrombosis Diff-Dx

Diagnosis:

Clinical symptoms & signs diagnosis of acute DVT
is not accurate due to its lack of sensitivity & specificity.

Lab. diagnosis:

Compression Duplex Doppler ultrasound of the proximal veins as the initial screening test for suspected DVT.
If the initial test results are normal, repeat ultrasound in 5 to 8 days.
D-dimer blood test is a useful adjunct for excluding DVT. See D-Dimer for DVT Screening Algorithm 2006
Usually used in combination with ultrasound. The laboratory results should be available within 2 hours of blood draw.
Consider MRV (magnetic resonance venography) if the diagnosis is equivocal after ultrasound or IPG.
Impedance plethysmography (IPG) for proximal DVT
This noninvasive test cannot distinguish acute DVT from other conditions that affect venous outflow, such as right-sided heart failure, peripheral arterial disease, or an external mass compressing the vein.
Venography of the leg is the gold standard in the diagnosis of DVT
This test can be of limited value if there is poor contrast filling of the deep veins, however it is the historical criterion standard for DVT

Different Diagnostic Approach to diagnosis of DVT:

May initially screen DVT with D-dimer blood test. If negative & without high clinical suspicion for DVT - stop further testing.
May initially screen DVT with compression Doppler ultrasound,
- if negative ultrasound, along with negative D-Dimer test - stop further testing.
- if negative ultrasound, but positive D-Dimer test - may do leg venography
- or if negative ultrasound initially, may repeat ultrasound in 5-8 days.

Drug Therapy

Use heparin and warfarin to treat acute proximal DVT, and consider thrombolysis for patients with iliofemoral DVT.

Give intravenous unfractionated (standard) heparin as a first-line therapy for DVT in hospitalized patients.
Possible dosing regimens are:

Initial bolus of unfractionated heparin of 5000 units followed by 1000 units per hour IV infusion
to achieve an APTT ratio 1.5 to 2.5 times normal
A weight-based approach, in which an 80 U/kg bolus is followed by an 18 U/kg·hour infusion.
Antidote for bleeding is protamine sulfate. One milligram of protamine neutralizes 90 U of heparin activity.

Consider outpatient therapy using subcutaneous LMWH (Low Molecular Weight Heparin) to treat acute DVT.
One of the following LMWH preparations:

Enoxaparin: 1 mg/kg subcutaneously every 12 hours, or 1.5 mg/kg subcutaneously every 24 hours
Tinzaparin: 175 IU/kg subcutaneously once daily

Consider the following LMWH regimens for DVT prophylaxis:

Enoxaparin: 30 mg subcutaneously every 12 hours
Dalteparin: 2500 U daily for abdominal surgery; 5000 U daily for high-risk patients
Danaparoid: 750 U subcutaneously every 12 hours
Ardeparin: 50 U/kg subcutaneously every 12 hours

Use long-term oral warfarin to reduce the risk of recurrent venous thromboembolism unless it is contraindicated.

Begin warfarin (initial dose 5 to 10 mg) as soon as anticoagulation is achieved with heparin and determine duration of therapy based on patient risk factors.
Continue heparin concomitantly with warfarin until the therapeutic potential of warfarin is achieved for 2 consecutive days.
Aim for an INR of 2 to 3.
Duration of Warfarin therapy:
3 months if there are major transient risk factors
6 months or until risk factor resolves if there is minor risk factor; no thrombophilia
6 months if there is an idiopathic event with no thrombophilia or low-risk thrombophilia
Indefinite duration if an idiopathic event with high-risk thrombophilia
Indefinite duration if more than one idiopathic event
Indefinite duration if cancer and other ongoing risk factor

Consider giving an IV or catheter-directed thrombolytic drug Alteplase tPA - tissue plasminogen activator to treat iliofemoral DVT.
Consider contraindications to thrombolysis carefully.
(urokinase is no longer available)

Consider giving recombinant hirudin to treat acute DVT for patients with heparin-induced thrombocytopenia (HIT).

Loading: 0.4 mg/kg iv; Maintenance: 0.15 mg/kg·h
Monitor r-hirudin anticoagulation with ecarin clotting time assay.

Consider LMWH (Enoxaparin, 1.5 mg/kg·d ) for secondary prevention of venous thromboembolism in patients with underlying cancer.

REF: ACP PIER 2005

Revisiting the Past Strengthens the Present:
An Evidence-Based Medicine Approach for the Diagnosis of Deep Venous Thrombosis
Russell D. Hull, MBBS, MSc EDITORIAL
Annals of Internal Medicine 5 April 2005 | Volume 142 Issue 7 | Pages 583-585

The clinical diagnosis of venous thrombosis is inaccurate because the clinical findings are both insensitive and nonspecific (1). The specificity of clinical diagnosis is low because the symptoms or signs can all be caused by nonthrombotic disorders. ....
Since the pretest probability plays a pivotal role in test selection and interpretation, a well-recorded history and careful physical examination are crucial parts of the diagnostic pathway.

The next step in developing an evidence-based approach is to understand the natural history of deep venous thrombosis.
Is embolic risk conditioned by location of deep venous thrombosis (3, 4)? The practical answer is yes.
Distal (calf) deep venous thrombosis poses a low risk for embolization, in contrast to the high risk with proximal (thigh) thrombi (3).
Proximal venous thrombosis requires antithrombotic therapy.
With deep venous thrombosis confined to the calf, it is safe to perform serial noninvasive testing and use antithrombotic therapy only for patients whose thrombus subsequently extends into the thigh (3, 5). When deep venous thrombosis is suspected clinically and confirmed by objective testing, 70% or more of patients have deep venous thrombosis in the popliteal or more proximal veins (6-9).

Accuracy studies and management studies are 2 differing but key methodologic approaches to diagnosing deep venous thrombosis. Accuracy studies (10) measure sensitivity and specificity by comparing noninvasive testing with the gold standard, contrast venography, whereas management studies determine the safety of withholding anticoagulant therapy if test findings are normal (10, 11).

Because compression ultrasonography is sensitive and specific for proximal deep venous thrombosis in symptomatic patients (10), it is now the usual diagnostic approach, although it often misses calf thrombi.

Management studies show that withholding anticoagulant therapy is safe if a serial ultrasonography result is negative (10).
High-quality evidence supports serial compression ultrasonography (12, 13) on presentation and, if the result is negative for proximal deep venous thrombosis on initial testing, a single repeated test performed 5 to 7 days later to detect proximal extension of calf thrombi. ........
Performing compression ultrasonography only twice is less onerous for the patient and is just as safe. Hospital practice trends over 2 decades show that compression ultrasonography has replaced ascending contrast venography (14).

In this issue, Kearon and colleagues (13) now provide further compelling evidence that withholding anticoagulant therapy is safe after normal results on initial and repeated compression ultrasonography at 1 week.
They report a randomized, multicenter management trial comparing an experimental strategy (perform a D-dimer test, then no further testing if the result is negative or venography if the result is positive) with the control strategy of repeated ultrasonography at 1 week. To be eligible, all 810 patients had a normal result on initial compression ultrasonography for the proximal veins. Although using venography after a positive D-dimer result revisits the past, it completes diagnostic testing in 1 day. Kearon and colleagues hypothesized that the experimental strategy would obviate the need for follow-up ultrasonography after 1 week and result in fewer cases of symptomatic venous thromboembolism during follow-up.

Their results are striking: 19 of 408 patients (4.7%) in the D-dimer group and 3 of 402 patients (0.7%) in the repeated ultrasonography group were initially diagnosed with deep venous thrombosis (P < 0.001). Surprisingly, the rate of symptomatic venous thromboembolism during follow-up was similar between the groups rather than lower in the experimental group. The rate was 2.1% (95% CI, 0.9% to 4.0%) in the experimental strategy group and 1.3% (CI, 0.4% to 2.9%) in the repeated ultrasonography group. Accordingly, although the experimental approach requires only 1 visit to resolve diagnostic uncertainty, it has no advantage in safety. Furthermore, venography may have several liabilities, including renal impairment, contrast dye allergy, and relatively low-quality venographic images in clinical practice as compared with the research setting.

The failure of the venographic strategy (13) to reduce the frequency of symptomatic venous thromboembolism during follow-up affirms the findings of earlier clinical studies (3, 15). The findings are consistent with a randomized study comparing a venographic surrogate with serial impedance plethysmography, which was effective and safe, despite a substantially lower initial detection rate (15). Noninvasive testing had a relatively low detection rate largely because it was compared with an increased rate of detecting isolated calf venous thrombosis by the venography (or equivalent) strategy (13, 15). Kearon and colleagues (13) thus provide further evidence that isolated calf venous thrombosis does not present a clinical threat for clinically evident pulmonary embolism unless it extends proximally.

Kearon and colleagues' study was well-conducted, with a relatively low rate of deviations from the study protocols and a low rate of loss to follow-up. A blinded central adjudication committee classified all suspected outcome events and deaths. The low prevalence of deep venous thrombosis (7.5%) in the study sample reduced the study's power to detect subsequent breakthrough venous thromboembolism during follow-up. Accordingly, Kearon and colleagues revised and increased the sample size. Despite sample size concerns, the low frequency of recurrent venous thromboembolism for the serial ultrasonography group (1.3% with an upper 95% confident limit of 2.9%) is reassuring evidence of safety.

In aggregate, the literature supports a multibranching pathway for diagnosing deep venous thrombosis and identifying patients for whom withholding anticoagulant therapy is safe (16, 17). Patients probably prefer a definitive answer in 1 visit and prefer noninvasive testing to contrast venography. Using only ultrasonography (12, 13) imposes a burden if the initial test result is negative. The patient must return for repeated evaluation 1 week later and must live with uncertainty for this week, and failure to return for follow-up can lead to a bad outcome. Kearon and colleagues (13) have shown that a strategy requiring 1 visit using ultrasonography, D-dimer testing, and venography offers a relatively safe outcome. This strategy avoids the need for venography in up to 75% of patients (13) by using it only after a negative result on initial ultrasonography and a positive D-dimer test result.

The D-dimer assay has come of age in routine practice. Physicians can limit the need for ultrasonography (16, 17) by using clinical probabilities, D-dimer testing, or both to rule out suspected deep venous thrombosis.

When a sensitive D-dimer assay result (16), such as a quantitative rapid enzyme-linked immunosorbent assay, is negative and the patient has a low or moderate pretest probability, ultrasonography is usually not needed.

Alternatively, with an initial normal result on ultrasonography, a negative D-dimer result (13, 16) will avoid the need for repeated ultrasonography, allowing definitive single-visit testing in many patients. Kearon and colleagues' study (13) used the D-dimer assay to limit patient exposure to venography to less than 25% of patients with a negative result on initial ultrasonography.

Currently, venography (13), which historically has been replaced by ultrasonography, will be a challenge for most diagnostic imaging departments because of lack of recent experience with the procedure. To avoid a high frequency of inadequate venography, radiologists will have to implement intensive quality control measures if they decide to reintroduce venography into routine practice for selected patients, as suggested by Kearon and colleagues (13).

How should clinicians choose a diagnostic strategy for suspected venous thrombosis?

Several key variables will determine the diagnostic pathway. The clinical setting (whether the patient is an inpatient or outpatient), the patients' comorbid condition (such as renal impairment), and expected adherence for repeated testing are important considerations. The availability, feasibility, and adequate quality of diagnostic testing (for example, adequate venography) are other key factors. Importantly, the physician should be alert to the patient's preferences. A strong preference for noninvasive testing will help determine which branch to take in the diagnostic algorithm. Kearon and colleagues' study opens our eyes to another diagnostic strategy for ruling out suspected deep venous thrombosis. Although this strategy lacks clear superiority, it is a safe alternative for patients who prefer a "one-stop" diagnosis rather than the proven, established noninvasive pathway (10, 12, 13, 16, 17).

References

From University of Calgary, Foothills Hospital, Calgary, Alberta T2N 2T9, Canada.

1. Mclachlin J, Richards T, Paterson JC. An evaluation of clinical signs in the diagnosis of venous thrombosis. Arch Surg. 1962;85:738-44. [PMID: 13932125].[Medline]

2. Wells PS, Hirsh J, Anderson DR, Lensing AW, Foster G, Kearon C, et al. Accuracy of clinical assessment of deep-vein thrombosis. Lancet. 1995;345:1326-30. [PMID: 7752753].[Medline]

3. Moser KM, LeMoine JR. Is embolic risk conditioned by location of deep venous thrombosis? Ann Intern Med. 1981;94:439-44. [PMID: 7212500].[Medline]

4. Kakkar VV, Howe CT, Flanc C, Clarke MB. Natural history of postoperative deep-vein thrombosis. Lancet. 1969;2:230-2. [PMID: 4184105].[Medline]

5. Tapson VF, Carroll BA, Davidson BL, Elliott CG, Fedullo PF, Hales CA, et al. The diagnostic approach to acute venous thromboembolism.Clinical practice guideline. American Thoracic Society. Am J Respir Crit Care Med. 1999;160:1043-66. [PMID: 10471639].[Free Full Text]

6. Cogo A, Lensing AW, Prandoni P, Hirsh J. Distribution of thrombosis in patients with symptomatic deep vein thrombosis. Implications for simplifying the diagnostic process with compression ultrasound. Arch Intern Med. 1993;153:2777-80. [PMID: 8257253].[Abstract]

7. Hull R, Hirsh J, Sackett DL, Powers P, Turpie AG, Walker I. Combined use of leg scanning and impedance plethysmography in suspected venous thrombosis. An alternative to venography. N Engl J Med. 1977;296:1497-500. [PMID: 865529].[Abstract]

8. Agnelli G, Longetti M, Cosmi B, Lupattelli L, Barzi F, Levi M, et al. Diagnostic accuracy of computerized impedance plethysmography in the diagnosis of symptomatic deep vein thrombosis: a controlled venographic study. Angiology. 1990;41:559-64. [PMID: 2202230].[Medline]

9. Heijboer H, Cogo A, Büller HR, Prandoni P, ten Cate JW. Detection of deep vein thrombosis with impedance plethysmography and real-time compression ultrasonography in hospitalized patients. Arch Intern Med. 1992;152:1901-3. [PMID: 1520059].[Abstract]

10. Kearon C, Julian JA, Newman TE, Ginsberg JS. Noninvasive diagnosis of deep venous thrombosis. McMaster Diagnostic Imaging Practice Guidelines Initiative. Ann Intern Med. 1998;128:663-77. [PMID: 9537941].[Abstract/Free Full Text]

11. Hull R, Hirsh J, Sackett DL, Taylor DW, Carter C, Turpie AG, et al. Clinical validity of a negative venogram in patients with clinically suspected venous thrombosis. Circulation. 1981;64:622-5. [PMID: 7261292].[Abstract]

12. Birdwell BG, Raskob GE, Whitsett TL, Durica SS, Comp PC, George JN, et al. The clinical validity of normal compression ultrasonography in outpatients suspected of having deep venous thrombosis. Ann Intern Med. 1998;128:1-7. [PMID: 9424975].[Abstract/Free Full Text]

13. Kearon C, Ginsberg JS, Douketis J, Crowther MA, Turpie AG, Bates SM, et al. A randomized trial of diagnostic strategies after normal proximal vein ultrasonography for suspected deep venous thrombosis: D-dimer testing compared with repeated ultrasonography. Ann Intern Med. 2005;142:490-6.[Abstract/Free Full Text]

14. Stein PD, Hull RD, Ghali WA, Patel KC, Olson RE, Meyers FA, et al. Tracking the uptake of evidence: two decades of hospital practice trends for diagnosing deep vein thrombosis and pulmonary embolism. Arch Intern Med. 2003;163:1213-9. [PMID: 12767959].[Abstract/Free Full Text]

15. Hull RD, Hirsh J, Carter CJ, Jay RM, Ockelford PA, Buller HR, et al. Diagnostic efficacy of impedance plethysmography for clinically suspected deep-vein thrombosis. A randomized trial. Ann Intern Med. 1985;102:21-8. [PMID: 3881068].[Medline]

16. Stein PD, Hull RD, Patel KC, Olson RE, Ghali WA, Brant R, et al. D-dimer for the exclusion of acute venous thrombosis and pulmonary embolism: a systematic review. Ann Intern Med. 2004;140:589-602. [PMID: 15096330].[Abstract/Free Full Text]

17. Wells PS, Anderson DR, Rodger M, Forgie M, Kearon C, Dreyer J, et al. Evaluation of D-dimer in the diagnosis of suspected deep-vein thrombosis. N Engl J Med. 2003;349:1227-35. [PMID: 14507948].[Abstract/Free Full Text]

Diagnosis	Pain	Skin Condition	Location

Acute SX < 72 hrs
DVT	+/-	warm, red	calf to thigh
Cellulitis	+	streaky redness	anywhere
Gastrocnemius rupture	+	blue (usually under medial malleolus)	medial aspect midcalf
Popliteal cyst	+/-	blue (usually under medial malleolus)	knee & calf
Erythema nodosum	++	erythematous nodules	below knee
Compartment syndrome	++	tough or douhy	typically below knee

Chronic SX > 72 hrs
Chronic venous infufficiency	+	golden brown color	typically below knee
lymphedema	_	dry & scaly peau d'orange, painless nonpitting edema	entire leg
RSD- Reflex sympathetic dystrophy	++	early, indurated; late, taut	regional distribution
Congenital venous malformation	+/-	port wine nevus	below knee