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Scope and methodology

  1. Top of page
  2. Scope and methodology
  3. Definition of terms
  4. Pulmonary embolism and lower limb DVT
  5. Guidance statements
  6. Guidance statements
  7. Hormone-associated PE and DVT
  8. Guidance statements
  9. Upper limb DVT
  10. Guidance statements
  11. Disclosure of Conflict of Interests
  12. References

This document gives guidance on deciding the duration of anticoagulation after a first episode of an unprovoked pulmonary embolus (PE) and/or deep vein thrombosis (DVT). Unprovoked PE and DVT are defined as those occurring in the absence of an antecedent (within 3 months) surgical or non-surgical risk factor [1]. Patients with an unprovoked PE and DVT account for 25% to 50% of all patients with venous thromboembolism. The guidance statements herein do not apply to patients with an unprovoked thrombosis in unusual sites, such as the splanchnic or intracerebral veins, or cancer-associated venous thrombosis.

The guidance in this document must be distinguished from a guideline based on a systematic literature review, which it is not. Such guidelines have previously been published [2]. Rather, this guidance outlines factors that may influence decision-making in individual patients with reference to published evidence-based guidelines. In addition, the guidance recognizes that factors not yet included in clinical guidelines, such as measurement of post-anticoagulation D-dimer or residual vein obstruction (RVO) after a DVT may still be used by some clinicians. The use of these factors in the decision-making process is not mandatory but guidance is given on appropriate use should clinicians choose to consider them.

The guidance statements included in this document are predicated on the following premises:

  • 1
     For each of the clinical situations described herein, our guidance statements are applicable to an average patient with a DVT and/or PE. There may be exceptional circumstances for which our guidance statements do not apply and anticoagulant management would be at the treating physician’s discretion.
  • 2
     The language used to reflect the strength of our guidance statements adopts the convention used in the GRADE (Grades of Recommendation Assessment, Development and Evaluation) system [3,4].
  • 3
     The wording ‘we recommend’ reflects a strong guidance statement, whereby the clinician should adopt the practice in most cases.
  • 4
     The wording ‘we suggest’ reflects a weak guidance statement, whereby the clinician may adopt the practice in some cases and that an alternative practice also may be acceptable.

Definition of terms

  1. Top of page
  2. Scope and methodology
  3. Definition of terms
  4. Pulmonary embolism and lower limb DVT
  5. Guidance statements
  6. Guidance statements
  7. Hormone-associated PE and DVT
  8. Guidance statements
  9. Upper limb DVT
  10. Guidance statements
  11. Disclosure of Conflict of Interests
  12. References

The definitions of duration of anticoagulation are:

  • 1
    Initial anticoagulation: 3–6 months of treatment;
  • 2
    Long-term (indefinite) anticoagulation: > 3–6 months of treatment with no definite ‘stop time’ which could be either lifelong or until the perceived bleeding risk precludes continuation of anticoagulation.

Pulmonary embolism and lower limb DVT

  1. Top of page
  2. Scope and methodology
  3. Definition of terms
  4. Pulmonary embolism and lower limb DVT
  5. Guidance statements
  6. Guidance statements
  7. Hormone-associated PE and DVT
  8. Guidance statements
  9. Upper limb DVT
  10. Guidance statements
  11. Disclosure of Conflict of Interests
  12. References

A period of adequate vitamin K antagonist (VKA) anticoagulation with a target international normalized ratio (INR) of 2.5 (range 2–3), as recommended by the American College of Chest Physicians [2], is required to prevent extension of thrombus and prevent early recurrence (within the first 3 to 6 months). Thereafter, long-term anticoagulation is required to prevent late recurrence. The benefit of anticoagulation continues only for as long as therapy is continued [5]. Consequently, long-term anticoagulation may, in effect, equate to lifelong treatment, or for as long as the perceived risk of anticoagulant therapy-related bleeding is not so high as to preclude continued treatment. This is referred to as ‘indefinite anticoagulation’ in the 2008 ACCP guidelines [2]. Therefore, when deciding the duration of oral anticoagulant therapy in an individual patient with a PE or DVT there are two issues to consider:

  • 1
     For how long should initial anticoagulant therapy last?
  • 2
     Thereafter, is the risk of recurrence sufficiently high and the risk of bleeding sufficiently low to justify continued long-term (indefinite) anticoagulant therapy?

Duration of initial anticoagulation

At least 3 months of therapeutic intensity anticoagulant therapy is required to prevent extension of thrombus and prevent early recurrence in patients after a first PE and/or proximal DVT (i.e. involvement of popliteal or more proximal veins) [5]. However, 6 months of initial anticoagulation of patients with unprovoked PE or proximal DVT appears to offer a lower risk of early recurrence than 3 months of treatment [5]. Patients with unprovoked isolated distal (calf vein) DVT have a risk of recurrence that is about half that of a proximal DVT or PE with anticoagulation for 6 weeks to 3 months, and the recurrence rate after 3 months of anticoagulation appears to be lower than with shorter duration treatment [5].

Guidance statements

  1. Top of page
  2. Scope and methodology
  3. Definition of terms
  4. Pulmonary embolism and lower limb DVT
  5. Guidance statements
  6. Guidance statements
  7. Hormone-associated PE and DVT
  8. Guidance statements
  9. Upper limb DVT
  10. Guidance statements
  11. Disclosure of Conflict of Interests
  12. References
  • 1
     We suggest that patients with an unprovoked calf DVT should be treated for 3 months.
  • 2
     We recommend that patients with an unprovoked PE or proximal DVT should be treated for 3 to 6 months.

Continued anticoagulation beyond the initial 3- to 6-month period

It is now clear that the circumstances in which a PE and DVT occur is the strongest predictor of likelihood of recurrence and determining this from the history is the most useful method of stratifying patient risk. Patients with unprovoked venous thrombosis have an annual risk of recurrence > 5% [1]. Given that this risk exceeds the risk of VKA-related bleeding, patients with a first or recurrent episode of unprovoked PE or proximal DVT should be considered for long-term anticoagulation. The American College of Chest Physicians has recommended that patients with an unprovoked proximal DVT, and/or PE, should be treated initially with 3 months anticoagulant therapy and then considered for long-term (potentially lifelong) anticoagulation depending on their risk of bleeding [2].

Patients with a PE and DVT provoked by surgery are at low risk of recurrence (annual risk < 1%) after completion of 3-months treatment with a VKA [1,6]. Anticoagulant therapy for longer than 3 months is not routinely required. Patients with a PE or DVT associated with non-surgical risk factors have a variable risk of recurrence, which is between that observed in patients with an initial unprovoked venous thromboembolism (VTE) or those provoked by surgery (see Table 2 in reference [1] for a comprehensive definition of provoking factors). The duration of anticoagulation should be influenced by the perceived risk in individual patients. However, we suggest long-term anticoagulant therapy generally be reserved for patients with no identifiable antecedent risk factor.

Patients with DVT confined to the calf have a lower risk of recurrence than patients presenting with a proximal DVT [5] and have a low risk of a recurrent VTE presenting as a PE [7].

Guidance statements

  1. Top of page
  2. Scope and methodology
  3. Definition of terms
  4. Pulmonary embolism and lower limb DVT
  5. Guidance statements
  6. Guidance statements
  7. Hormone-associated PE and DVT
  8. Guidance statements
  9. Upper limb DVT
  10. Guidance statements
  11. Disclosure of Conflict of Interests
  12. References
  • 1
     We suggest that in patients with an unprovoked calf DVT (i.e. not extending into the popliteal vein) anticoagulant therapy for longer than 3 months is not required.
  • 2
     We suggest that in patients with an unprovoked PE or proximal DVT anticoagulation should be considered for as long as the perceived risk of anticoagulant-related bleeding (see below) is not so high as to preclude continued treatment.
  • 3
     We suggest that in patients with a provoked PE and DVT anticoagulant therapy after 3 months is not required.

See also Guidance Statements under Other Factors to Predict Risk of Recurrence.

Hormone-associated PE and DVT

  1. Top of page
  2. Scope and methodology
  3. Definition of terms
  4. Pulmonary embolism and lower limb DVT
  5. Guidance statements
  6. Guidance statements
  7. Hormone-associated PE and DVT
  8. Guidance statements
  9. Upper limb DVT
  10. Guidance statements
  11. Disclosure of Conflict of Interests
  12. References

This can be defined as a PE or DVT occurring in women who are receiving estrogen-containing hormonal therapy (oral contraceptive and estrogen replacement therapy) and do not have additional risk factors. There is a difference of opinion between experts as to whether a VTE in these women should be considered as unprovoked or not. However, in women with a hormone-associated PE or DVT the prognosis is generally good after a 3- to 6-month period of anticoagulant therapy with an approximately 50% lower risk for thrombosis recurrence compared with women with an unprovoked VTE occurring in the absence of hormonal use [8].

Women who develop a hormone-associated PE or DVT are in general advised to stop this preparation. However, continuation of an estrogen-containing preparation may be warranted for selected patients, for example patients with strong gynecological indications or a personal preference for hormonal treatment, combined with continued anticoagulant therapy. Although there are no clinical trials (randomized or not) assessing the safety of continuing hormonal therapy plus anticoagulant therapy after a PE or DVT, continuation is probably safe (without an increase in recurrence) because any prothrombotic effect of hormonal therapy is likely to be suppressed by therapeutic-intensity anticoagulation.

Guidance statements

  1. Top of page
  2. Scope and methodology
  3. Definition of terms
  4. Pulmonary embolism and lower limb DVT
  5. Guidance statements
  6. Guidance statements
  7. Hormone-associated PE and DVT
  8. Guidance statements
  9. Upper limb DVT
  10. Guidance statements
  11. Disclosure of Conflict of Interests
  12. References
  • 1
     We recommend that anticoagulant therapy for longer than 3 months is not required for women with a hormone-associated VTE if hormone therapy is stopped at the time of diagnosis.
  • 2
     We recommend that women diagnosed with a hormone-associated VTE discontinue hormonal therapy (oral contraceptive and estrogen replacement) before stopping anticoagulant therapy; however, in premenopausal women an effective alternative contraception must be utilized to avoid the potential toxicity of early fetal warfarin exposure.
  • 3
     We suggest that hormonal therapy can be continued in selected patients if there is a strong clinical indication for such treatment but anticoagulant therapy should be continued for the duration of hormonal therapy.

Risk of bleeding and quality of anticoagulant therapy

Major determinants of bleeding as a result of VKA therapy include: (i) advanced age; (ii) previous bleeding; (iii) increased (or variable) intensity of anticoagulation; (iv) comorbidities such as renal or hepatic impairment; (v) concomitant use of drugs that affect hemostasis, such as aspirin or clopidogrel; and (vi) duration of therapy [9]. The risk of oral anticoagulant-associated bleeding is likely to be low in:

  • 1
     patients with a target INR of 2.5 (range 2.0–3.0) compared with a higher target;
  • 2
     younger patients, particularly under 70 years of age;
  • 3
     patients who do not require long-term treatment with drugs that affect hemostasis (e.g. ASA, clopidogrel and NSAIDs);
  • 4
     patients who have not had episodes of overanticoagulation or suffered bleeding during the initial 3 to 6 months of therapy;
  • 5
     patients who understand anticoagulant treatment e.g. those who follow dose instructions, have regular INR monitoring, are aware of food and drug interactions, comply with more frequent monitoring during periods of intercurrent illness or initiation of other medications.

In a meta-analysis of VKA-associated bleeding among patients with VTE, the rate of major hemorrhage was 2.06% (equivalent to about 9% per year) during the initial 3 months of therapy; after the first 3 months the rate was 2.7 per 100 patient-years (2.7% per year). The rate of intracranial hemorrhage was 1.48 per 100 patient-years during the initial 3 months of therapy but decreased to 0.65 per 100 patient-years thereafter [10]. The likelihood of a hemorrhage (and recurrent venous thrombosis) was related to the INR time in range in a retrospective study of 2300 patients [11]. In that study, the risk of haemorrhage was lowest in patients spending at least 45% of time in range. As the time in range during the initial 30 days was predictive of future INR control, one approach to assessing patients’ risk of VKA-related bleeding associated with continued treatment may involve reviewing the quality of anticoagulation during the initial treatment period, either by formally calculating the time in range (we suggest a time in range of less than 50% is inadequate) or alternatively identifying patients with INRs greater than 5.0, after completion of the VKA initiation period. This approach, although sensible, requires validation in future studies.

The safety of anticoagulation should also take into account the case-fatality rate of recurrent thrombosis and major bleeding. Thus, in patients who are receiving VKA therapy, the case fatality of VKA-associated bleeding (both during the initial 3 months and subsequent period) is ∼9% [10]. On the other hand, in patients who stop VKA therapy, the case-fatality of recurrent VTE is ∼5% [12,13].

Other factors to predict risk of recurrence

D-dimer  While the overall risk for thrombosis recurrence in patients with a previous unprovoked PE or DVT is about 10% in the first year after a minimum of 3 months of anticoagulant therapy, individual risk is heterogeneous. This is illustrated by a lower annual risk in patients with a low D-dimer result after completion of initial VKA therapy compared with those with a high D-dimer (∼4% vs.∼ 9%) [14–16]. If D-dimer is done, it is reasonable to do so 3–4 weeks after stopping anticoagulation to ensure no residual effect of anticoagulation on the D-dimer level and to minimize the time patients are off treatment. Overall, exactly how D-dimer measurement should be used is still under investigation. D-dimer assays have different performance characteristics and only D-dimer methods validated by clinical management studies should be used to strongly influence clinical decisions.

Residual vein occlusion  Residual vein occlusion, as detected by venous ultrasound, does not predict a likelihood of a recurrent DVT to a degree that is clinically useful [17,18].

Post-thrombotic Syndrome  In a prospective cohort study, post-thrombotic syndrome (PTS) was associated with a 2.6-fold increased risk of recurrence after unprovoked DVT [19]. This risk is similar to that observed in patients with a high D-dimer. PTS is associated with a high D-dimer [20] and it is as yet unknown if the presence of PTS has a predictive value independent of D-dimer measurement.

Thrombophilia  Testing for heritable thrombophilic defects does not usefully predict likelihood of thrombosis recurrence after a first episode of VTE and for this reason testing for heritable thrombophilia is not routinely required [21]. Testing for heritable thrombophilias in selected patients, such as those with a strong family history of unprovoked recurrent thrombosis, may influence decisions regarding duration of anticoagulation. However, it is not possible to give a validated guidance statement as to how such patients should be selected as a family history is a poor predictor of likelihood of identifying a heritable thrombophilic defect [22].

Male gender  Males appear to be at 1.8-fold higher risk of recurrence after an episode of an unprovoked VTE although a mechanism to explain this observation has not been elucidated [8].

Mode of clinical presentation  Although patients presenting with symptoms of a DVT are as likely to develop thrombosis recurrence as patients presenting with symptoms of PE, the mode of initial presentation appears to predict the mode of thrombosis recurrence. Patients with an initial unprovoked PE are three to four times more likely to suffer recurrence as a PE rather than DVT [7,23,24] and the risk of a fatal PE is two to four times more likely in patients with a symptomatic PE as compared with patients with a symptomatic DVT alone [13,25,26]. Consequently, continued anticoagulation is an appropriate consideration in selected patients who initially present with a PE, particularly patients with a limited cardiorespiratory reserve in whom a recurrent PE may be life threatening.

Ideally, these and other putative predictors of thrombosis recurrence should be incorporated into a clinical decision guide to stratify patients according to the risk for recurrent VTE. Several guides have been proposed but require independent validation before they can be considered for use in everyday clinical practice [27–29].

Guidance statements

  • 1
     It is not possible to give a definitive guidance statement as to which patients should or should not receive long-term anticoagulant therapy after an episode of an unprovoked PE or DVT. Patients should be assessed on an individual basis, taking into consideration factors contributing to thrombosis recurrence risk and bleeding risk, and should be offered information outlining the risks and benefits of long-term anticoagulation. Moreover, patients’ values and preferences should be considered, relating to the impact of thrombosis recurrence (if anticoagulation is stopped) and bleeding (if anticoagulation is continued).
  • 2
     We suggest that the following factors may favor long-term anticoagulation in patients with a first unprovoked PE or DVT:
    • a
        male gender;
    • b
        moderate-to-severe post-thrombotic syndrome;
    • c
        ongoing dyspnoea (possibly related to unresolved or recurrent PE);
    • d
        satisfactory initial anticoagulant control;
    • e
        elevated D-dimer result based on individual D-dimer assay performance characteristics using a study-validated assay.
  • 3
     We suggest that the following factors may favor stopping anticoagulation in patients with a first unprovoked VTE:
    • a
        female gender;
    • b
        absent or mild post-thrombotic syndrome;
    • c
        unsatisfactory initial anticoagulant control;
    • d
        low D-dimer result based on individual D-dimer assay performance characteristics using a study-validated assay.

Upper limb DVT

  1. Top of page
  2. Scope and methodology
  3. Definition of terms
  4. Pulmonary embolism and lower limb DVT
  5. Guidance statements
  6. Guidance statements
  7. Hormone-associated PE and DVT
  8. Guidance statements
  9. Upper limb DVT
  10. Guidance statements
  11. Disclosure of Conflict of Interests
  12. References

Initial anticoagulant therapy for venous thrombosis of the upper limb is the same as for the lower limb. Randomized trials of different durations of anticoagulation have not been performed. Most cases of an upper limb DVT are provoked by central venous catheters. The development of a DVT should not necessitate the removal of a central venous catheter, especially when it remains functional and can be used to administer medically necessary treatment. There is evidence from observational studies that this approach may be safe and efficacious [30].

Long-term VKA therapy is not routinely required even if a DVT is unprovoked as the recurrence rate appears to be low (< 5%) in first year after anticoagulation is discontinued [31,32]. Risk factors that may indicate consideration of continued anticoagulation include a persistent thoracic outlet syndrome, severe post-thrombotic syndrome or the continued use of an indwelling central venous catheter. As thoracic outlet syndrome is a risk factor for an upper limb DVT, imaging studies, such as CT or MR venography of the affected vasculature, can be useful to define the site of obstruction. Vascular surgical intervention can be undertaken for severe thoracic outlet syndrome to obviate consideration of continued anticoagulation.

Guidance statements

  1. Top of page
  2. Scope and methodology
  3. Definition of terms
  4. Pulmonary embolism and lower limb DVT
  5. Guidance statements
  6. Guidance statements
  7. Hormone-associated PE and DVT
  8. Guidance statements
  9. Upper limb DVT
  10. Guidance statements
  11. Disclosure of Conflict of Interests
  12. References
  • 1
     We suggest that patients with an unprovoked upper limb DVT should be treated for 3 months initially.
  • 2
     We suggest that long-term anticoagulant therapy is not routinely used in patients with an upper limb DVT in the absence of continuing risk factors.
  • 3
     We suggest that continued anticoagulation should be considered in patients with an indwelling central venous catheter, persistent thoracic outlet syndrome or severe post-thrombotic syndrome.

References

  1. Top of page
  2. Scope and methodology
  3. Definition of terms
  4. Pulmonary embolism and lower limb DVT
  5. Guidance statements
  6. Guidance statements
  7. Hormone-associated PE and DVT
  8. Guidance statements
  9. Upper limb DVT
  10. Guidance statements
  11. Disclosure of Conflict of Interests
  12. References
  • 1
    Iorio A, Kearon C, Filippucci E, Marcucci M, Macura A, Pengo V, Siragusa S, Palareti G. Risk of recurrence after a first episode of symptomatic venous thromboembolism provoked by a transient risk factor: a systematic review. Arch Intern Med 2010; 170: 17106.
  • 2
    Kearon C, Kahn SR, Agnelli G, Goldhaber S, Raskob GE, Comerota AJ. Antithrombotic therapy for venous thromboembolic disease: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines (8th Edition). Chest 2008; 133: 454S545S.
  • 3
    Guyatt GH, Oxman AD, Kunz R, Falck-Ytter Y, Vist GE, Liberati A, Schunemann HJ. Going from evidence to recommendations. Br Med J 2008; 336: 104951.
  • 4
    Guyatt GH, Oxman AD, Vist GE, Kunz R, Falck-Ytter Y, Alonso-Coello P, Schunemann HJ. GRADE: an emerging consensus on rating quality of evidence and strength of recommendations. Br Med J 2008; 336: 9246.
  • 5
    Boutitie F, Pinede L, Schulman S, Agnelli G, Raskob G, Julian J, Hirsh J, Kearon C. Influence of preceding length of anticoagulant treatment and initial presentation of venous thromboembolism on risk of recurrence after stopping treatment: analysis of individual participants’ data from seven trials. Br Med J 2011; 342: d3036.
  • 6
    Kearon C, Iorio A, Palareti G. Risk of recurrent venous thromboembolism after stopping treatment in cohort studies: recommendation for acceptable rates and standardized reporting. J Thromb Haemost 2010; 8: 23135.
  • 7
    Baglin T, Douketis J, Tosetto A, Marcucci M, Cushman M, Kyrle P, Palareti G, Poli D, Tait RC, Iorio A. Does the clinical presentation and extent of venous thrombosis predict likelihood and type of recurrence? A patient-level meta-analysis J Thromb Haemost 2010; 8: 243642.
  • 8
    Douketis J, Tosetto A, Marcucci M, Baglin T, Cosmi B, Cushman M, Kyrle P, Poli D, Tait RC, Iorio A. Risk of recurrence after venous thromboembolism in men and women: patient level meta-analysis. Br Med J 2011; 342: d813.
  • 9
    Schulman S, Beyth RJ, Kearon C, Levine MN. Hemorrhagic complications of anticoagulant and thrombolytic treatment: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines (8th Edition). Chest 2008; 133: 257S98S.
  • 10
    Linkins LA, Choi PT, Douketis JD. Clinical impact of bleeding in patients taking oral anticoagulant therapy for venous thromboembolism: a meta-analysis. Ann Intern Med 2003; 139: 893900.
  • 11
    Veeger NJ, Piersma-Wichers M, Tijssen JG, Hillege HL, van der Meer J. Individual time within target range in patients treated with vitamin K antagonists: main determinant of quality of anticoagulation and predictor of clinical outcome. A retrospective study of 2300 consecutive patients with venous thromboembolism. Br J Haematol 2005; 128: 5139.
  • 12
    Carrier M, Le Gal G, Wells PS, Rodger MA. Systematic review: case-fatality rates of recurrent venous thromboembolism and major bleeding events among patients treated for venous thromboembolism. Ann Intern Med 2010; 152: 57889.
  • 13
    Douketis JD, Gu CS, Schulman S, Ghirarduzzi A, Pengo V, Prandoni P. The risk for fatal pulmonary embolism after discontinuing anticoagulant therapy for venous thromboembolism. Ann Intern Med 2007; 147: 76674.
  • 14
    Cosmi B, Palareti G. Update on the predictive value of D-dimer in patients with idiopathic venous thromboembolism. Thromb Res 2010; 125(Suppl. 2): S625.
  • 15
    Douketis J, Tosetto A, Marcucci M, Baglin T, Cushman M, Eichinger S, Palareti G, Poli D, Tait RC, Iorio A. Patient-level meta-analysis: effect of measurement timing, threshold, and patient age on ability of D-dimer testing to assess recurrence risk after unprovoked venous thromboembolism. Ann Intern Med 2010; 153: 52331.
  • 16
    Verhovsek M, Douketis JD, Yi Q, Shrivastava S, Tait RC, Baglin T, Poli D, Lim W. Systematic review: D-dimer to predict recurrent disease after stopping anticoagulant therapy for unprovoked venous thromboembolism. Ann Intern Med 2008; 149: 48190, W94.
  • 17
    Carrier M, Rodger MA, Wells PS, Righini M, Le Gal G. Residual vein obstruction to predict the risk of recurrent venous thromboembolism in patients with deep vein thrombosis: a systematic review and meta-analysis. J Thromb Haemost 2011; 9: 111925.
  • 18
    Le Gal G, Carrier M, Kovacs MJ, Betancourt MT, Kahn SR, Wells PS, Anderson DA, Chagnon I, Solymoss S, Crowther M, Righini M, Delluc A, White RH, Vickars L, Rodger M. Residual vein obstruction as a predictor for recurrent thromboembolic events after a first unprovoked episode: data from the REVERSE cohort study. J Thromb Haemost 2011; 9: 112632.
  • 19
    Stain M, Schonauer V, Minar E, Bialonczyk C, Hirschl M, Weltermann A, Kyrle PA, Eichinger S. The post-thrombotic syndrome: risk factors and impact on the course of thrombotic disease. J Thromb Haemost 2005; 3: 26716.
  • 20
    Latella J, Desmarais S, Miron MJ, Roussin A, Joyal F, Kassis J, Solymoss S, Desjardins L, Ginsberg JS, Kahn SR. Relation between D-dimer level, venous valvular reflux and the development of post-thrombotic syndrome after deep vein thrombosis. J Thromb Haemost 2010; 8: 216975.
  • 21
    Baglin T, Gray E, Greaves M, Hunt BJ, Keeling D, Machin S, Mackie I, Makris M, Nokes T, Perry D, Tait RC, Walker I, Watson H. Clinical guidelines for testing for heritable thrombophilia. Br J Haematol 2010; 149: 20920.
  • 22
    van Sluis GL, Sohne M, El Kheir DY, Tanck MW, Gerdes VE, Buller HR. Family history and inherited thrombophilia. J Thromb Haemost 2006; 4: 21827.
  • 23
    Murin S, Romano PS, White RH. Comparison of outcomes after hospitalization for deep venous thrombosis or pulmonary embolism. Thromb Haemost 2002; 88: 40714.
  • 24
    Schulman S, Lindmarker P, Holmstrom M, Larfars G, Carlsson A, Nicol P, Svensson E, Ljungberg B, Viering S, Nordlander S, Leijd B, Jahed K, Hjorth M, Linder O, Beckman M. Post-thrombotic syndrome, recurrence, and death 10 years after the first episode of venous thromboembolism treated with warfarin for 6 weeks or 6 months. J Thromb Haemost 2006; 4: 73442.
  • 25
    Douketis JD, Kearon C, Bates S, Duku EK, Ginsberg JS. Risk of fatal pulmonary embolism in patients with treated venous thromboembolism. JAMA 1998; 279: 45862.
  • 26
    Laporte S, Mismetti P, Decousus H, Uresandi F, Otero R, Lobo JL, Monreal M. Clinical predictors for fatal pulmonary embolism in 15,520 patients with venous thromboembolism: findings from the Registro Informatizado de la Enfermedad TromboEmbolica venosa (RIETE) Registry. Circulation 2008; 117: 17116.
  • 27
    Eichinger S, Heinze G, Jandeck LM, Kyrle PA. Risk assessment of recurrence in patients with unprovoked deep vein thrombosis or pulmonary embolism: the Vienna prediction model. Circulation 2010; 121: 16306.
  • 28
    Rodger MA, Kahn SR, Wells PS, Anderson DA, Chagnon I, Le Gal G, Solymoss S, Crowther M, Perrier A, White R, Vickars L, Ramsay T, Betancourt MT, Kovacs MJ. Identifying unprovoked thromboembolism patients at low risk for recurrence who can discontinue anticoagulant therapy. Can Med Assoc J 2008; 179: 41726.
  • 29
    Tosetto A, Iorio A, Marcucci M, Baglin T, Cushman M, Eichinger S, Palareti G, Poli D, Tait C, Douketis J. Predicting Disease Recurrence in Patients with Previous Unprovoked Venous Thromboembolism: the DASH Prediction Score. Blood 2011; 118: 544.
  • 30
    Kovacs MJ, Kahn SR, Rodger M, Anderson DR, Andreou R, Mangel JE, Morrow B, Clement AM, Wells PS. A pilot study of central venous catheter survival in cancer patients using low-molecular-weight heparin (dalteparin) and warfarin without catheter removal for the treatment of upper extremity deep vein thrombosis (The Catheter Study). J Thromb Haemost 2007; 5: 16503.
  • 31
    Flinterman LE, van Hylckama Vlieg A, Rosendaal FR, Doggen CJ. Recurrent thrombosis and survival after a first venous thrombosis of the upper extremity. Circulation 2008; 118: 136672.
  • 32
    Martinelli I, Battaglioli T, Bucciarelli P, Passamonti SM, Mannucci PM. Risk factors and recurrence rate of primary deep vein thrombosis of the upper extremities. Circulation 2004; 110: 56670.