Deep vein thrombosis: Difference between revisions

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===Imaging the leg veins===
===Imaging the leg veins===
Compression [[medical ultrasonography|ultrasound]] scanning of the leg veins, combined with duplex measurements (to determine blood flow), can reveal a [[blood clot]] and its extent (i.e. whether it is below or above the [[knee]]).
Compression [[medical ultrasonography|ultrasound]] scanning of the leg veins, combined with duplex measurements (to determine blood flow), can reveal a [[blood clot]] and its extent (i.e. whether it is below or above the [[knee]]).
Either whole leg ultrasound or serial 2-point ultrasonography plus D-dimer are equivalent strategies according to a [[randomized controlled trial]].<ref name="pmid18840838">{{cite journal |author=Bernardi E, Camporese G, Büller HR, ''et al'' |title=Serial 2-point [[ultrasonography]] plus [[D-dimer]] vs whole-leg color-coded Doppler [[ultrasonography]] for diagnosing suspected symptomatic deep vein thrombosis: a randomized controlled trial |journal=JAMA : the journal of the American Medical Association |volume=300 |issue=14 |pages=1653–9 |year=2008 |month=October |pmid=18840838 |doi=10.1001/jama.300.14.1653 |url=http://jama.ama-assn.org/cgi/pmidlookup?view=long&pmid=18840838 |issn=}}</ref>


===Blood tests===
===Blood tests===

Revision as of 13:13, 4 November 2008

Deep vein thrombosis [r]: The formation of a blood clot ("thrombus") in a deep vein. [e]

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Template:TOC-right Deep-vein thrombosis, also known as deep-venous thrombosis (DTV), is the formation of a blood clot ("thrombus") in a deep vein. It commonly affects the leg veins, such as the femoral vein or the popliteal vein or the deep veins of the pelvis. Occasionally the veins of the arm are affected (known as Paget-Schrötter disease). Embolism and thrombosis is the more general class of pathologies of this kind.

Thrombi may develop first in the calf veins, "growing" in the direction of flow of the vein. DVTs are distinguished as being above or below the popliteal vein. Very extensive DVTs can extend into the iliac veins or the inferior vena cava. The risk of pulmonary embolism is higher in the presence of more extensive clots.

Epidemiology

DVTs occur in about 1 per 1000 persons per year. About 1-5% will die from the complications (i.e. pulmonary embolism).

DVT is much less common in the pediatric population. About 1 in 100,000 people under the age of 18 experiences deep vein thrombosis, possibly due to a child's high rate of heartbeats per minute, relatively active lifestyle when compared with adults, and fewer comorbodities (e.g. malignancy).

Cause/etiology

Virchow's triad

Many factors are involved in the formation of a thrombus (clot). Virchow's triad is a group of 3 factors known to affect clot formation: rate of flow, the consistency (thickness) of the blood, and qualities of the vessel wall. Among the risk factors are advanced age, obesity, infection, immobilization, female sex, use of oral contraceptives, tobacco usage and air travel ("economy class syndrome", a combination of immobility and relative dehydration) are some of the better-known causes.[1] Thrombophilia (tendency to develop thrombosis) often expresses itself with recurrent thromboses.

Underlying malignancy

DVT may be due to underlying malignancy, especially if the DVT is associated with older age, idiopathic DVT, bilateral thrombosis, or anemia.[2] These patients have a worse prognosis.

Genetics

A twin study found a genetic contribution to venous thromboembolism among men but not women.[3] Among men, the concordance rates for mono- and dizygotic twin pairs were 0.22 and 0.08.

Various single-nucleotide polymorphisms (SNPs) have been associated with DVT.[4]

Signs and symptoms

There may be no symptoms referrable to the location of the DVT, but the classical symptoms of DVT include pain, swelling and redness of the leg and dilatation of the surface veins. In up to 25% of all hospitalized patients, there may be some form of DVT, which often remains clinically inapparent (unless pulmonary embolism develops).

There are several techniques during physical examination to increase the detection of DVT, such as measuring the circumference of the affected and the contralateral limb at a fixed point (to objectivate edema), and palpating the venous tract, which is often tender. Physical examination is unreliable for excluding the diagnosis of deep vein thrombosis.

A careful history has to be taken considering risk factors (see below), including the use of estrogen-containing methods of hormonal contraception, recent long-haul flying, and a history of miscarriage (which is a feature of several disorders that can also cause thrombosis). A family history can reveal a hereditary factor in the development of DVT.

It is vital that the possibility of pulmonary embolism be included in the history, as this may warrant further investigation (see pulmonary embolism).

Complications As a complication, post-thrombotic syndrome can develop. Post-phlebitic syndrome occurs in 10% of patients with deep vein thrombosis (DVT). It presents with leg oedema, pain, nocturnal cramping, venous claudication, skin pigmentation, dermatitis and ulceration (usually on the medial aspect of the lower leg). In phlegmasia alba dolens, the leg is pale and cool with a diminished arterial pulse due to spasm. It usually results from acute occlusion of the iliac and femoral veins due to DVT. In phlegmasia cerulea dolens, there is an acute and nearly total venous occlusion of the entire extremity outflow, including the iliac and femoral veins. The leg is usually painful, cyanosed and oedematous. Venous gangrene may supervene.

Diagnosis

Homan's sign is used in clinical practice to diagnose DVT.

The gold standard is intravenous venography, which involves injecting a peripheral vein of the affected limb with a contrast agent and taking X-rays, to reveal whether the venous supply has been obstructed. Because of its invasiveness, this test is rarely performed.

Impedance plethysmography and Doppler ultrasonography are non-invasive alternatives.

Probability scoring

Wells rule

The best studied clinical prediction rule is the Wells rule; however, use of the Wells rule is complicated by the rule having been modified over time. This has resulted in guidelines recommending use of outdated versions of the Wells rule.[5] The rule was introduced in 1995.[6]

1995 Original Wells 12 point rule:[6]
Major points

  • Active cancer (treatment ongoing or within previous 6 months or palliative)
  • Paralysis, paresis. or recent plaster irnmobilisation of the lower extremities
  • Recently bedridden >3 days and/or major surgery within 4 weeks
  • Localised tenderness along tl’e distribution of the deep venous system
  • Thigh and calf swollen (should be measured)
  • Calf swelling 3cm >symptornless side (measured 10cm below tibial tuberosity
  • Strong family history of (NT (2 first degree relatives with history of CVI)

Minor points

  • History of recent trauma C 60 days) to the symptomatic leg
  • Pitting oedema; symptomatic leg only
  • Dilated superficial veins (non-varicose) in symptomatic leg only
  • Hospitisation within previous 6 months
  • Erythema

1997 Wells 9 point rule:[7]

  1. Active cancer (treatment ongoing or within previous 6 months or palliative) - 1 point
  2. Paralysis, paresis, or recent plaster immobilisation of the lower extremities - 1 point
  3. Recently bedridden for more than 3 days or major surgery, within 4 weeks - 1 point
  4. Localised tenderness along the distribution of the deep venous system - 1 point
  5. Entire leg swollen - 1 point
  6. Calf swelling by more than 3 cm when compared with the asymptomatic leg (measured 10 cm below tibial tuberosity) - 1 point
  7. Pitting oedema (greater in the symptomatic leg) - 1 point
  8. Collateral superficial veins (non-varicose) - 1 point
  9. Alternative diagnosis as likely or greater than that of deep-vein thrombosis - subtract 2 points
Interpretation: low (score 0), medium (score of 1 or 2), or high (score 3)

In 2005 a large study found that the 1997 Wells score failed to adequately exclude DVT in primary care patients.[8] Unfortunately, the 2005 study was completed in March, 2003, 6 months prior to publication of the 2003 revision by Wells to his rule in which he added a 10th variable.

In 2003, Wells published a 10 point rule that adds a point for history of previous DVT.[9] In 2006, Wells reviewed the available clinical prediction rules for DVT and did not further modify the 2003 rule.[10]

2003[9]-2006[10] Wells 10 point rule:

  1. Active cancer (treatment within last 6 months or palliative) -- 1 point
  2. Calf swelling >3cm compared to other calf (measured 10cm below tibial tuberosity) -- 1 point
  3. Collateral superficial veins (non-varicose) -- 1 point
  4. Pitting edema (confined to symptomatic leg) -- 1 point
  5. Swelling of entire leg - 1 point
  6. Localized pain along distribution of deep venous system -- 1 point
  7. Paralysis, paresis, or recent cast immobilization of lower extremities -- 1 point
  8. Recently bedridden > 3 days, or major surgery requiring regional or general anesthetic in past 12 weeks -- 1 point
  9. Previously documented DVT -- 1 point
  10. Alternative diagnosis at least as likely -- Subtract 2 points
Interpretation:
Score of 2 or higher - deep vein thrombosis is likely. Consider imaging the leg veins.
Score of less than 2 - deep vein thrombosis is unlikely. Consider blood test such as d-dimer test to further rule out deep vein thrombosis.

Based one his 2003 study, Wells recommends that DVT is excluded only when the 10-point score is < 2 and the D-dimer is negative.[10]

Oudega rule

Because of concerns about the failed study in 2005 of the older, 9-point 1997 Wells rule (note that the current Wells rule has 10 points)[8], Oudega developed a rule with 7 clinical variable plus the D-dimer.[11] This rule has not been externally validated by independent research groups.

Imaging the leg veins

Compression ultrasound scanning of the leg veins, combined with duplex measurements (to determine blood flow), can reveal a blood clot and its extent (i.e. whether it is below or above the knee).

Either whole leg ultrasound or serial 2-point ultrasonography plus D-dimer are equivalent strategies according to a randomized controlled trial.[12]

Blood tests

In a low-probability situation, current practice is to commence investigations by testing for D-dimer levels. This cross-linked fibrin degradation product is an indication that thrombosis is occurring, and that the blood clot is being dissolved by plasmin. A low D dimer level should prompt other possible diagnoses (such as a ruptured Baker's cyst, if this has not been considered as part of the history).

Other blood tests usually performed at this point are:

Prophylaxis (Prevention)

Clinical practice guidelines by the American College of Chest Physicians (ACCP) provide recommendations on DVT prophylaxis in hospitalized patients [13].

New clinical practice guidelines by the American College of Chest Physicians (ACCP) were published in 2008.[14]

General Medical Inpatients

Regarding general medical inpatients the 2008 guidelines state:

  • "For acutely ill medical patients admitted to hospital with congestive heart failure or severe respiratory disease, or who are confined to bed and have one or more additional risk factors, including active cancer, previous VTE, sepsis, acute neurologic disease, or inflammatory bowel disease, we recommend thromboprophylaxis with LMWH (Grade 1A), LDUH (Grade 1A), or fondaparinux (Grade 1A)."

Enoxaparin or unfractionated heparin may be used.[15] LMWH may be more effective than UFH. If UFH heparin is used, 5000 U 3 times daily may be more effective[16]

Since publication of the ACCP guidelines, an additional randomized controlled trial [17] and meta-analysis [18] including the trial have been published. The meta-analysis concluded " Anticoagulant prophylaxis is effective in preventing symptomatic venous thromboembolism during anticoagulant prophylaxis in at-risk hospitalized medical patients. Additional research is needed to determine the risk for venous thromboembolism in these patients after prophylaxis has been stopped." With regards to which patients are at risk, most studies in the meta-analysis were of patients with New York Heart Association Functional Classification (NYHA) III-IV heart failure. Regarding patients at lesser risk of DVT, the trial above[17] and an earlier trial[19] are relevant yet inconclusive.

Oncology patients

According to a clinical practice guideline by the American Society of Clinical Oncology, "all hospitalized cancer patients should be considered for VTE prophylaxis with anticoagulants in the absence of bleeding or other contraindications."[20]

Surgery Patients

In patients who have undergone surgery, low molecular weight heparins (LMWH) are routinely administered to prevent thrombosis. LMWH can only currently be administered subcutaneously by injection. Prophylaxis for pregnant women who have a history of thrombosis may be limited to LMWH injections or may not be necessary if their risk factors are mainly temporary.

Early and regular ambulation (walking) is a treatment that predates anticoagulants and is still recognized and used today. Walking activates the body's muscle pumps, increasing venous velocity and preventing stasis. Intermittent pneumatic compression (IPC) machines have proven protective in bed- or chair-ridden patients at very high risk or with contraindications to heparins. IPC machines use air bladders that are wrapped around the thigh and/or calf. The bladders alternately inflate and deflate, squeezing the muscles and increasing blood velocity by as much as 500%. IPC machines have been proven effective on knee and hip surgery patients (a population with a risk as high as 80% with no prophylactic treatment) of developing DVT and PE. Alternatively, between 150-300mg of aspirin can be taken.

Travelers

There is clinical evidence to suggest that wearing compression socks while traveling also reduces the incidence of thrombosis in people on long haul flights. A randomized study in 2001 compared two sets of long haul airline passengers, one set wore travel compression hosiery the others did not. The passengers were all scanned and blood tested to check for the incidence of DVT. The results showed that asymptomatic DVT occurred in 10% of the passengers who did not wear compression socks. The group wearing compression had no DVTs. The authors concluded that wearing elastic compression hosiery reduces the incidence of DVT in long haul airline passengers.[21].

Therapy

Treatment options have been reviewed.[22]

  • Anticoagulation is the usual treatment for DVT. In general, patients are initiated on a brief course (i.e., less than a week) of heparin treatment while they start on a 3- to 6-month course of warfarin (or related vitamin K inhibitors). Low molecular weight heparin (LMWH) is preferred,[24] though unfractionated heparin is given in patients who have a contraindication to LMWH (e.g., renal failure or imminent need for invasive procedure).

Regarding the duration of anticoagulation, see embolism and thrombosis: treatment.

  • Elastic compression stockings should be routinely applied.[24] The stockings in almost all trials were stronger than routine anti-embolism stockings and created either 20-30 mm Hg or 30-40 mm Hg. Most trials used knee-high stockings. A meta-analysis of randomized controlled trials by the Cochrane Collaboration showed reduced incidence of post-phlebitic syndrome.[25] The number needed to treat is quite potent at 4 to 5 patients need to prevent one case of post-phlebitic syndrome.[26]
  • Inferior vena cava filter reduces pulmonary embolism[27] and is an option for patients with an absolute contraindiciation to anticoagulant treatment (e.g., cerebral hemorrhage) or those rare patients who have objectively documented recurrent PEs while on anticoagulation, an inferior vena cava filter (also referred to as a Greenfield filter) may prevent pulmonary embolisation of the leg clot. However these filters are themselves potential foci of thrombosis,[28] IVC filters are viewed as a temporizing measure for preventing life-threatening pulmonary embolism.
  • Hospitalization should be considered in patients with more than two of the following risk factors as these patients may have more risk of complications during treatment[29]:
    • bilateral DVT, renal insufficiency, body weight <70 kg, recent immobility, chronic heart failure, and cancer

Oncology patients

A clinical practice guideline published in 2004 by the American College of Chest Physicians states:[30]

"for patients with DVT and cancer, we recommend LMWH for the first 3 to 6 months of long-term anticoagulant therapy (Grade 1A). For these patients, we recommend anticoagulant therapy indefinitely or until the cancer is resolved".

A clinical practice guideline published in 2007 by the American Society of Clinical Oncology states:[20]

"1) low molecular weight heparin LMWH is the preferred approach for the initial 5 to 10 days of anticoagulant treatment of the cancer patient with established VTE, 2) LMWH given for at least 6 months is also the preferred approach for long-term anticoagulant therapy. Vitamin K antagonists with a targeted INR of 2 to 3 are acceptable for long-term therapy when LMWH is not available. 3) After 6 months, indefinite anticoagulant therapy should be considered for selected patients with active cancer, such as those with metastatic disease and those receiving chemotherapy. This recommendation is based on Panel consensus in the absence of clinical trials data."

See also

References

  1. ↑ Tsai A, Cushman M, Rosamond W, Heckbert S, Polak J, Folsom A (2002). "Cardiovascular risk factors and venous thromboembolism incidence: the longitudinal investigation of thromboembolism etiology.". Arch Intern Med 162 (10): 1182-9. PMID 12020191.
  2. ↑ Trujillo-Santos J, Prandoni P, Rivron-Guillot K, et al (2008). "Clinical outcome in patients with venous thromboembolism and hidden cancer: findings from the RIETE Registry". J Thromb Haemost 6 (2): 251–255. DOI:10.1111/j.1538-7836.2007.02837.x. PMID 18021305. Research Blogging.
  3. ↑ Larsen TB, Sørensen HT, Skytthe A, Johnsen SP, Vaupel JW, Christensen K (2003). "Major genetic susceptibility for venous thromboembolism in men: a study of Danish twins". Epidemiology 14 (3): 328-32. PMID 12859034. [e]
  4. ↑ Bezemer, I. D., Bare, L. A., Doggen, C. J. M., Arellano, A. R., Tong, C., Rowland, C. M., et al. (2008). Gene variants associated with deep vein thrombosis, JAMA, 299(11), 1306-1314. DOI:10.1001/jama.299.11.1306.
  5. ↑ Qaseem A, Snow V, Barry P, et al (2007). "Current diagnosis of venous thromboembolism in primary care: a clinical practice guideline from the American Academy of Family Physicians and the American College of Physicians". Ann. Intern. Med. 146 (6): 454–8. PMID 17371890. [e]
  6. ↑ 6.0 6.1 Wells PS, Hirsh J, Anderson DR, et al (1995). "Accuracy of clinical assessment of deep-vein thrombosis". Lancet 345 (8961): 1326–30. PMID 7752753. [e]
  7. ↑ Wells PS, Anderson DR, Bormanis J, et al (1997). "Value of assessment of pretest probability of deep-vein thrombosis in clinical management". Lancet 350 (9094): 1795–8. DOI:10.1016/S0140-6736(97)08140-3. PMID 9428249. Research Blogging.
  8. ↑ 8.0 8.1 Oudega R, Hoes AW, Moons KG (2005). "The Wells rule does not adequately rule out deep venous thrombosis in primary care patients". Ann. Intern. Med. 143 (2): 100–7. PMID 16027451. [e] Cite error: Invalid <ref> tag; name "pmid16027451" defined multiple times with different content
  9. ↑ 9.0 9.1 Wells PS, Anderson DR, Rodger M, et al (2003). "Evaluation of D-dimer in the diagnosis of suspected deep-vein thrombosis". N. Engl. J. Med. 349 (13): 1227–35. DOI:10.1056/NEJMoa023153. PMID 14507948. Research Blogging.
  10. ↑ 10.0 10.1 10.2 Scarvelis D, Wells PS (2006). "Diagnosis and treatment of deep-vein thrombosis". CMAJ 175 (9): 1087–92. DOI:10.1503/cmaj.060366. PMID 17060659. Research Blogging.
  11. ↑ Toll, DB et al. 2008. “A new diagnostic rule for deep vein thrombosis: safety and efficiency in clinically relevant subgroups.” Fam. Pract. 2008. http://fampra.oxfordjournals.org/cgi/content/full/cmm075v1
  12. ↑ Bernardi E, Camporese G, Büller HR, et al (October 2008). "Serial 2-point ultrasonography plus D-dimer vs whole-leg color-coded Doppler ultrasonography for diagnosing suspected symptomatic deep vein thrombosis: a randomized controlled trial". JAMA : the journal of the American Medical Association 300 (14): 1653–9. DOI:10.1001/jama.300.14.1653. PMID 18840838. Research Blogging.
  13. ↑ Geerts WH, Pineo GF, Heit JA, Bergqvist D, Lassen MR, Colwell CW, Ray JG. Prevention of venous thromboembolism: the Seventh ACCP Conference on Antithrombotic and Thrombolytic Therapy. Chest. 2004 Sep;126 (3 Suppl):338S-400S. http://www.chestjournal.org/cgi/content/full/126/3_suppl/338S PMID 15383478
  14. ↑ Geerts, William H.; David Bergqvist, Graham F. Pineo, John A. Heit, Charles M. Samama, Michael R. Lassen, Clifford W. Colwell (2008-06-01). "Prevention of Venous Thromboembolism: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines (8th Edition)". Chest 133 (6_suppl): 381S-453. DOI:10.1378/chest.08-0656. Retrieved on 2008-06-24. Research Blogging.
  15. ↑ King CS, Holley AB, Jackson JL, Shorr AF, Moores LK (2007). "Twice vs three times daily heparin dosing for thromboembolism prophylaxis in the general medical population: A metaanalysis". Chest 131 (2): 507–16. PMID 17296655.
  16. ↑ Wein L et al. Pharmacological Venous Thromboembolism Prophylaxis in Hospitalized Medical Patients. Arch Intern med 2007;167:1476-1486.
  17. ↑ 17.0 17.1 Lederle FA, Sacks JM, Fiore L, Landefeld CS, Steinberg N, Peters RW, Eid AA, Sebastian J, Stasek JE Jr, Fye CL. The prophylaxis of medical patients for thromboembolism pilot study. Am J Med. 2006;119:54-9. PMID 16431185
  18. ↑ Dentali F, Douketis JD, Gianni M, Lim W, Crowther MA. Meta-analysis: anticoagulant prophylaxis to prevent symptomatic venous thromboembolism in hospitalized medical patients. Ann Intern Med. 2007;146:278-88. PMID 17310052
  19. ↑ Gärdlund B (1996). "Randomised, controlled trial of low-dose heparin for prevention of fatal pulmonary embolism in patients with infectious diseases. The Heparin Prophylaxis Study Group". Lancet 347 (9012): 1357–61. PMID 8637340. [e]
  20. ↑ 20.0 20.1 Lyman GH, Khorana AA, Falanga A, et al (2007). "American Society of Clinical Oncology Guideline: Recommendations for Venous Thromboembolism Prophylaxis and Treatment in Patients With Cancer". DOI:10.1200/JCO.2007.14.1283. PMID 17968019. Research Blogging. Cite error: Invalid <ref> tag; name "pmid17968019" defined multiple times with different content
  21. ↑ Scurr JH, Machin SJ, Bailey-King S, Mackie IJ, McDonald S, Smith PD. Frequency and prevention of symptomless deep-vein thrombosis in long-haul flights: a randomised trial. Lancet 2001;12(9267):1485-9. PMID 11377600.
  22. ↑ Bates SM, Ginsberg JS (July 2004). "Clinical practice. Treatment of deep-vein thrombosis". N. Engl. J. Med. 351 (3): 268–77. DOI:10.1056/NEJMcp031676. PMID 15254285. Research Blogging.
  23. ↑ Watson L, Armon M. "Thrombolysis for acute deep vein thrombosis". Cochrane Database Syst Rev: CD002783. PMID 15495034.
  24. ↑ 24.0 24.1 Snow V et al (2007). "Management of Venous Thromboembolism: A Clinical Practice Guideline from the American College of Physicians and the American Academy of Family Physicians". Ann Intern Med 146 (3). Cite error: Invalid <ref> tag; name "pmid0000" defined multiple times with different content
  25. ↑ Kolbach D, Sandbrink M, Hamulyak K, Neumann H, Prins M. "Non-pharmaceutical measures for prevention of post-thrombotic syndrome". Cochrane Database Syst Rev: CD004174. DOI:10.1002/14651858.CD004174.pub2. PMID 14974060. Research Blogging.
  26. ↑ Kakkos S, Daskalopoulou S, Daskalopoulos M, Nicolaides A, Geroulakos G (2006). "Review on the value of graduated elastic compression stockings after deep vein thrombosis". Thromb Haemost 96 (4): 441-5. PMID 17003920.
  27. ↑ Decousus H, Leizorovicz A, Parent F, Page Y, Tardy B, Girard P, Laporte S, Faivre R, Charbonnier B, Barral F, Huet Y, Simonneau G (1998). "A clinical trial of vena caval filters in the prevention of pulmonary embolism in patients with proximal deep-vein thrombosis. Prévention du Risque d'Embolie Pulmonaire par Interruption Cave Study Group". N Engl J Med 338 (7): 409-15. PMID 9459643.
  28. ↑ (2005) "Eight-year follow-up of patients with permanent vena cava filters in the prevention of pulmonary embolism: the PREPIC (Prevention du Risque d'Embolie Pulmonaire par Interruption Cave) randomized study". Circulation 112 (3): 416-22. PMID 16009794.
  29. ↑ Trujillo-Santos J, Herrera S, Page MA, et al (2006). "Predicting adverse outcome in outpatients with acute deep vein thrombosis. findings from the RIETE Registry". J. Vasc. Surg. 44 (4): 789-93. DOI:10.1016/j.jvs.2006.06.032. PMID 16926081. Research Blogging.
  30. ↑ Büller HR, Agnelli G, Hull RD, Hyers TM, Prins MH, Raskob GE (2004). "Antithrombotic therapy for venous thromboembolic disease: the Seventh ACCP Conference on Antithrombotic and Thrombolytic Therapy". Chest 126 (3 Suppl): 401S–428S. DOI:10.1378/chest.126.3_suppl.401S. PMID 15383479. Research Blogging.

External links

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