Risk assessment for recurrent venous thrombosis

doi:10.1016/S0140-6736(10)60962-2

The Lancet

Volume 376, Issue 9757, 11–17 December 2010, Pages 2032-2039

https://doi.org/10.1016/S0140-6736(10)60962-2 Get rights and content

Summary

Venous thrombosis is a common disease that frequently recurs. Recurrence can be prevented by anticoagulants, albeit at the cost of bleeding. Thus, assessment of the risk of recurrence is important to balance the risks and benefits of anticoagulation treatment. Many clinical and laboratory risk factors for recurrent venous thrombosis have been established. Nevertheless, prediction of recurrence in an individual patient remains a challenge. Detection of some laboratory markers is associated with only a moderate risk of recurrence, and the relevance of others is not known. Many patients have several risk factors and the effect of combined defects is obscure. Routine screening for these laboratory markers should therefore be abandoned. Risk assessment can be improved by measurement of global markers that encompass the effects of clotting and fibrinolytic disorders. Analysis of preliminary data suggests that risk assessment can also be refined through integration of prothrombotic coagulation changes and clinical risk factors.

Introduction

Venous thrombosis is a common disease with a yearly incidence of around one case per 1000 person-years.1, 2 In a third of patients deep venous thrombosis is complicated by embolisation of the clot into the lungs. Short-term mortality from pulmonary embolism is high and mainly depends on age and presence of underlying comorbidities such as cancer or cardiorespiratory disease.2, 3 Results from a population-based study⁴ showed the 30-day mortality of pulmonary embolism was 28%. By contrast, a 30-day mortality of around 9% was reported in a large hospital-discharge dataset.⁵

Venous thrombosis is a chronic disease that often recurs. In unselected cohorts of patients with venous thrombosis, the risk of recurrence after 5 years is 20–25%, and is higher than 25% in patients with unprovoked venous thrombosis.6, 7, 8 Recurrence risk is mainly dependent on presence or absence of acquired and congenital risk factors and might vary substantially between patients. Results from one study⁹ suggested a case-fatality rate of recurrent venous thromboembolism of 5–12%, whereas data from a systematic review¹⁰ reported 3·6%. Standard treatment of acute venous thrombosis is heparin followed by vitamin K antagonists for several months, a regimen that almost wholly prevents recurrence, albeit at the cost of bleeding.¹ The risk of major bleeding in patients who are receiving anticoagulation treatment is around 3% per year in clinical trials and is higher in routine practice.11, 12, 13 The case-fatality rate of fatal bleeding in patients who were given anticoagulant treatment was reported to be 11·3%.¹⁰ Consequently, thrombotic risk assessment is of particular importance, as only patients at high risk of recurrence will benefit from long-term anticoagulation treatment, whereas patients at low risk will unnecessarily be exposed to a risk of bleeding. This Review discusses different approaches to risk assessment of recurrence of venous thrombosis in patients with deep vein thrombosis of the leg or pulmonary embolism after completion of anticoagulant treatment.

Section snippets

Risk factors for recurrent venous thrombosis

Until the late 1980s, risk of recurrent venous thrombosis was estimated on the basis of only a few patient characteristics, such as absence or presence of a triggering factor, concomitant pulmonary embolism, or previous venous thrombosis, and with the results of a few laboratory tests such as measurement of concentrations of antithrombin, protein C, and protein S. At that time, the natural course of venous thrombosis was poorly understood, and many risk factors of the disease were yet to be

Clinical features

Table 1 shows the clinical features associated with high risk of recurrent venous thrombosis. Risk of recurrence is especially high in patients in whom the initial venous thrombosis was unprovoked (ie, the event occurred in the absence of a temporary risk such as surgery, trauma, pregnancy, or taking of female hormones). Risk of recurrence was 25% in a cohort of patients from Austria¹⁴ with unprovoked venous thrombosis or pulmonary embolism 5 years after the incident event, and increased with

Laboratory markers

Table 2 shows laboratory-detectable markers associated with increased risk of recurrent venous thrombosis. Estimates of the risk of recurrence in patients with deficiencies of natural coagulation inhibitors, such as antithrombin, protein C, or protein S, are mainly derived from studies in families with highly penetrant thrombophilia. Risk of recurrence seems to be highest in patients with antithrombin deficiency.72, 73, 74, 75 In the Leiden Thrombophilia Study,²⁴ the hazard ratio of recurrent

Relevance of laboratory screening

Abnormalities that are associated with an increased risk of venous thrombosis, and that are detectable with laboratory techniques, can be established in more than 50% of patients with a first unprovoked venous thrombosis. Therefore, identification of these thrombophilic defects to improve patient care is a tempting prospect. Laboratory screening for thrombophilia has been repeatedly advocated88, 89 and is now done on a routine basis in many institutions around the world. Our Review of

Global markers of coagulation

Risk of venous thrombosis is increased with a high number of risk factors present in an individual. Global markers of coagulation, the concentrations of which might suggest multifactorial thrombophilia, could be used to estimate risk of recurrence. Patients with a short activated partial thromboplastin time have a higher risk of recurrence than do those with a short test time. Stratification of patients by recurrence risk can also be done with an assay that is based on partial thromboplastin

Clinical characteristics of patients and laboratory markers

A new approach for assessment of risk of recurrent venous thrombosis is combination of clinical characteristics of patients (eg, location of the thrombus, sex, or age) with laboratory testing. Rodger and colleagues³¹ studied 646 patients with a first, unprovoked venous thrombosis for 4 years. Through combination of four of 69 investigated risk factors (absence of symptoms suggestive of post-thrombotic syndrome, D-dimer concentration during anticoagulation treatment <250 ng/mL, body-mass index

Future considerations

In the past few decades, assessment of the risk of recurrence after an episode of venous thrombosis has substantially improved through understanding of the natural course of the disease and characterisation of factors that establish recurrence risk. However, we are not able to predict recurrence on the basis of laboratory abnormalities with enough precision to recommend implication of testing to clinical practice. Discovery of unknown risk factors in the (near) future will add to our ability to

Search strategy and selection criteria

We searched PubMed, the Cochrane Library, Medline, and AMEDEO for reports published in any language, without date restriction, with the search terms “deep vein thrombosis”, “venous thrombosis”, “pulmonary embolism”, and “venous thromboembolism” in combination with the terms “recurrent venous thrombosis”, “recurrent venous thromboembolism”, “recurrence”, “risk of recurrence”, “risk factors of recurrence”, “thrombophilia”, “prediction of recurrence”, and “prevention of recurrence”. We searched

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Cited by (227)

Anticoagulation strategies and long-term recurrence in patients with venous thromboembolism in the era of direct oral anticoagulants
2023, European Journal of Internal Medicine
There has been limited data on anticoagulation strategies and long-term recurrence in patients with venous thromboembolism (VTE) in the era of direct oral anticoagulant (DOAC).
The COMMAND VTE Registry-2 is a multicenter retrospective cohort study enrolling 5197 consecutive patients with acute symptomatic VTE between January 2015 and August 2020 among 31 centers in Japan. In this primary report, the entire cohort was divided into 5 groups; major transient risk factors (N = 475, 9.1%), minor transient risk factors (N = 788, 15%), unprovoked (N = 1913, 37%), non-malignant persistent risk factors (N = 514, 9.9%), and active cancer (N = 1507, 29%) groups.
DOACs were administered in 79% of patients who received oral anticoagulants. Discontinuation of anticoagulant at 1 year was most frequent in the major transient risk factors group (57.2%, 46.3%, 29.1%, 32.0%, and 45.6%). The cumulative 5-year incidence of recurrent VTE was lowest in the major transient risk factors group (2.6%, 6.4%, 11.0%, 12.1%, and 10.1%, P < 0.001). The cumulative 5-year incidence of major bleeding was highest in the active cancer group (9.8%, 11.4%, 11.0%, 15.5%, and 20.4%, P < 0.001). After discontinuation of anticoagulation therapy, the cumulative 5-year incidence of recurrent VTE was highest in the unprovoked group (3.3%, 11.0%, 24.9%, 17.5%, and 11.8%, P < 0.001).
In this large real-world VTE registry, anticoagulation strategies and long-term recurrence widely differed depending on the baseline characteristics. Detailed risk stratifications of recurrent VTE could be useful for decision-making of anticoagulation strategies, whereas the bleeding-risk assessment might be especially important in the era of DOAC.
URL: http://www.umin.ac.jp/ctr/index.htm Unique identifier: UMIN000044816.
Retinal vein occlusion, a great unknown and a challenge in venous thromboembolic disease
2023, Revista Clinica Espanola
Predicting the risk of recurrent venous thromboembolism: Impact and therapeutic consequences of inherited thrombophilia
2022, JMV-Journal de Medecine Vasculaire
Over the past decades, thrombophilia testing in patients with venous thrombo-embolism has increased tremendously. However, the role of inherited thrombophilie in prediction the risk of recurrence remains controversial. Consequently, it is still unclear whether thrombophilia testing influences decisions regarding duration of anticoagulation in clinical practices. The aim of this study was to evaluate the impact if inherited thrombophilia on venous thrombosis treatment decisions and on predicting the risk of recurrence.
A retrospective longitudinal study (January 2011-Decembre 2016) including 131 patients with confirmed venous thrombo-embolism referred to the hematology laboratory from the internal medicine department for inherited thrombophilia screening was carried out.
The mean age patients was 39.4 years and the sex ratio (M/F) was 0.61. Inherited thrombophilia was confirmed in 27.5% of patients. A long term anticoagulation was decided in 46.9% of patients with thrombophilia. There was no significant difference in the duration of anticoagulation between patients with or without thrombophilia. Thrombosis recurrence was recorded in 16 (17%) patients. The 24 years cumulative incidence of recurrence was 19% in patients with thrombophilia and 17% in those without (plog Rank= 0.6). Inherited thrombophilia was not associated with increased risk of recurrence after treatment withdrawal (Hazard ratio = 1.31 IC (0.47-3.63); P = 0.6).
In clinical practice, inherited thrombophilia did not influence anticoagulation duration and was not associated with a higher venous thrombosis risk of recurrence. It seems to be less relevant for decision making than presumed.
Severity of pulmonary embolism at initial diagnosis and long-term clinical outcomes: From the COMMAND VTE Registry
2021, International Journal of Cardiology
There is a paucity of data on the long-term clinical outcomes according to the severity of pulmonary embolism (PE) at initial diagnosis.
The COMMAND VTE Registry is a multicenter registry enrolling 3027 consecutive patients with acute symptomatic venous thromboembolism (VTE). After excluding 1312 patients without PE, the current study population consisted of 1715 patients with PE, who were divided into 3 groups according to the clinical severity; massive PE, sub-massive PE and low-risk PE.
There were 179 patients (10%) with massive PE, 742 patients (43%) with sub-massive PE, and 794 patients (46%) with low-risk PE. By the landmark analysis at 3 months, the cumulative incidences of recurrent VTE were similar among the 3 groups both within and beyond 3 months (Massive PE: 2.9%, Sub-massive PE: 4.2%, and Low-risk PE: 3.3%, P = 0.61, and 4.3%, 8.8%, and 7.8% at 5 years, P = 0.47, respectively). After adjusting confounders, the risk of massive PE relative to low-risk PE for recurrent VTE beyond 3 months remained insignificant (adjusted HR 0.54, 95% CI: 0.13–1.51, P = 0.27). Patients with massive PE at initial diagnosis more often presented as severe recurrent PE events than those with sub-massive and low-risk PE.
In the current real-world large registry, the long-term risk of overall recurrent VTE in patients with massive PE at initial diagnosis did not significantly differ from those with sub-massive and low-risk PE beyond 3 months, although patients with massive PE at initial diagnosis more frequently developed recurrent VTE as PE with severe clinical presentation.
Renal dysfunction and long-term clinical outcomes in patients with venous thromboembolism: From the COMMAND VTE Registry
2020, Thrombosis Research
Patients with renal dysfunction are at high risk for developing venous thromboembolism (VTE). However, the impact of renal dysfunction on recurrent VTE remains to be clarified. We assessed the relationship between estimated glomerular filtration rate (eGFR) at diagnosis and long-term clinical outcomes in VTE patients.
The COMMAND VTE Registry is a multicenter registry enrolling consecutive patients with acute symptomatic VTE among 29 centers in Japan between January 2010 and August 2014. Patients with available creatinine values (N = 2829) were divided into the reference eGFR (≥60 mL/min/1.73 m²) group (N = 1760) and the low eGFR (<60 mL/min/1.73 m²) group (N = 1069). The low eGFR group was further subdivided into the moderately low eGFR (30–59 mL/min/1.73 m²) group (N = 898) and very low eGFR (<30 mL/min/1.73 m²) group (N = 171).
The low eGFR group was independently associated with the increased risk for recurrent VTE (adjusted HR 1.55, 95%CI 1.15–2.08). When the low eGFR group was subdivided into the moderately low and very low eGFR groups, the risk for recurrent VTE increased with decreasing eGFR (adjusted HR 1.43, 95%CI 1.04–1.95, and adjusted HR 2.54, 95%CI 1.42–4.28). The risk for major bleeding was higher in the very low eGFR group, but not in the moderately low eGFR group (adjusted HR 1.70, 95%CI 1.06–2.61, and adjusted HR 0.85, 95%CI 0.73–1.28).
Renal dysfunction measured by eGFR was associated with an increased risk for recurrent VTE, which was more prominent in severe renal dysfunction. Severe renal dysfunction was also associated with a higher risk for major bleeding.
Validation of the VTE-BLEED score’s long-term performance for major bleeding in patients with venous thromboembolisms: From the COMMAND VTE registry
2020, Journal of Thrombosis and Haemostasis
The recently proposed VTE‐BLEED score to predict the risk of major bleeding in patients with venous thromboembolisms (VTEs) on prolonged anticoagulation therapy was validated externally in randomized controlled trials and in a selected cohort, but not applied in non‐selective cohorts.
The present study aimed to evaluate the generalizability of the VTE‐BLEED score in a non‐selective cohort.
The COMMAND VTE Registry is a multicenter retrospective registry enrolling consecutive patients with acute symptomatic VTEs among 29 centers in Japan. The present study population consisted of 2124 patients with prolonged anticoagulation therapy beyond 30 days, including 2008 (95%) patients with a first VTE episode and 1075 (51%) with unprovoked VTEs, who were divided into 1445 patients (68%) with a VTE‐BLEED score of ≥2 (high‐risk group) and 679 (32%) with a VTE‐BLEED score of <2 (low‐risk group).
During a median follow‐up period of 672 days, major bleeding events occurred in 121 patients. The cumulative 5‐year incidence of major bleeding beyond 30 days was significantly higher in the high‐risk group than low‐risk group (13.2% versus 5.4%, P < .001). The hazard function curves demonstrated that the hazards of the high‐risk group were consistently higher over time compared with the low‐risk group, which suggested the long‐term predictive ability of the score.
In the present real‐world VTE registry, the VTE‐BLEED score had a long‐term predictive ability for high‐risk patients with major bleeding during prolonged anticoagulation therapy, which could be useful in determining the optimal duration of anticoagulation therapy in individual patients.

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ReviewRisk assessment for recurrent venous thrombosis

Summary

Introduction

Section snippets

Risk factors for recurrent venous thrombosis

Clinical features

Laboratory markers

Relevance of laboratory screening

Global markers of coagulation

Clinical characteristics of patients and laboratory markers

Future considerations

Search strategy and selection criteria

Lancet

J Thromb Haemost

Lancet

Lancet

Lancet

Blood

Blood

J Thromb Haemost

J Thromb Haemost

J Thromb Haemost

J Thromb Haemost

Am J Med

Am J Med

Am J Med

J Thromb Haemost

Blood

J Thromb Haemost

Blood

J Thromb Haemost

J Thromb Haemost

Blood

J Vasc Surg

J Thromb Haemost

Blood

Chest

Blood

J Thromb Haemost

J Thromb Haemost

Lancet

The epidemiology of venous thromboembolism in the community

Thromb Haemost

A prediction rule to identify low-risk patients with pulmonary embolism

Arch Intern Med

Recurrent venous thromboembolism after deep vein thrombosis: incidence and risk factors

Arch Intern Med

The risk of recurrent venous thromboembolism after discontinuing anticoagulation in patients with acute proximal deep vein thrombosis or pulmonary embolism. A prospective cohort study in 1,626 patients

Haematologica

Age at first venous thromboembolism and risk of recurrence: a prospective cohort study

Medicine (Baltimore)

The risk for fatal pulmonary embolism after discontinuing anticoagulant therapy for venous thromboembolism

Ann Intern Med

Systematic review: case-fatality rates of recurrent venous thromboembolism and major bleeding events among patients treated for venous thromboembolism

Ann Intern Med

Clinical Impact of bleeding in patients taking oral anticoagulant therapy for venous thromboembolism

Ann Intern Med

Risk of major hemorrhage for outpatients treated with warfarin

J Gen Intern Med

A multicomponent intervention to prevent major bleeding complications in older patients receiving warfarin. A randomised, controlled trial

Ann Intern Med

Risk assessment of recurrence in patients with unprovoked deep model vein thrombosis or pulmonary embolism: the Vienna prediction model

Circulation

Symptomatic pulmonary embolism and the risk of recurrent venous thromboembolism

Arch Intern Med

The risk of recurrent venous thromboembolism in patients with unprovoked symptomatic deep vein thrombosis and asymptomatic pulmonary embolism

Thromb Haemost

Long-term, low intensity warfarin therapy for the prevention of recurrent venous thromboembolism

N Engl J Med

The risk of recurrent venous thromboembolism in men and women

N Engl J Med

Residual thrombosis on ultrasonography to guide the duration of anticoagulation in patients with deep venous thrombosis: a randomized trial

Ann Intern Med

Residual venous thrombosis as a predictive factor of recurrent venous thromboembolism

Ann Intern Med

Thrombophilia, clinical factors, and recurrent venous thrombotic events

JAMA

Increased risk of recurrent venous thromboembolism during hormone replacement therapy-results of the randomised, double-blind, placebo-controlled estrogen in venous thromboembolism trial (EVTET)

Thromb Haemost

Review
Risk assessment for recurrent venous thrombosis