Prospective Study of Natural History of Deep Vein Thrombosis: Early Predictors of Poor Late Outcomes

doi:10.1016/j.avsg.2012.09.018

Annals of Vascular Surgery

Volume 27, Issue 7, October 2013, Pages 924-931

https://doi.org/10.1016/j.avsg.2012.09.018 Get rights and content

Background

A proportion of patients with deep vein thrombosis (DVT) will develop postthrombotic syndrome (PTS). Currently, the only clearly identified risk factors for developing PTS are recurrent ipsilateral DVT and extensive proximal disease. The aim of the study was to assess the natural history of DVT and identify early predictors of poor clinical outcome at 5 years.

Methods

Patients with suspected acute DVT in the lower limb were assessed prospectively. All patients with a confirmed DVT were asked to participate in this study. Within 7–10 days after diagnosis of DVT, patients underwent a further review, involving clinical, ultrasound, and air plethysmography assessment of both lower limbs. Patients were reassessed at regular intervals for 5 years.

Results

One hundred twenty-two limbs in 114 patients were included in this study. Thrombus regression occurred in two phases, with a rapid regression between 10 days and 3 months, and a more gradual regression thereafter. Reflux developed as thrombus regression occurred. Segmental reflux progressed to axial deep reflux and continued to deteriorate in a significant proportion of patients with iliofemoral–popliteal–calf DVT throughout the 5-year study period. Similarly, venous filling index became progressively more abnormal, in this group, over the course of the study. Four risk factors for PTS were identified as best predictors: extensive clot load on presentation; <50% clot regression at 6 months; venous filling index >2.5 mL/sec; and abnormal outflow rate (<0.6). Patients with three or more of these risk factors had a significant risk of developing PTS with sensitivity 100%, specificity 83%, and positive predictive value 67%. Patients scoring 2 or less did not have PTS at 5 years with a negative predictive value of 100%.

Conclusions

This is the first study to show that venous assessment at 6 months post-DVT can predict PTS at 5 years. Those who will not develop PTS can be reassured of this at 6 months.

Introduction

Deep vein thrombosis (DVT) accounts for approximately 12% of all venous insufficiency syndromes in the community,¹ and the economic burden associated with postthrombotic syndrome (PTS) is considerable.² Although the natural history of DVT has been extensively followed during the short to mid-term, few studies have prospectively followed DVT patients for >2 years. Although PTS may develop during this time, the more severe changes associated with PTS (lipodermatosclerosis and ulceration) are likely to take longer to develop, and therefore their incidence may currently be underestimated.

The pathophysiology of PTS is thought to involve valvular incompetence due to inflammation and recanalization of the initial thrombus causing damage to the venous valves, and persistent outflow obstruction due to residual thrombus.³ Currently, the only clearly identified risk factors for developing PTS are extensive and recurrent ipsilateral DVT.4, 5, 6, 7, 8 Other risk factors previously described include obesity, clot lysis, reflux, and outflow obstruction.9, 10, 11, 12

Several studies have been conducted looking at the effect of prescribing compression stockings for patients in an effort to prevent or lessen the severity of PTS. Prandoni et al. found that compression stockings did indeed reduce the number of patients developing PTS from 49% in the control group to just 24% in the group with stockings. To prevent 1 case of PTS developing, 4 patients would need to be treated with elastic compression stockings for ≥2 years.¹³

Compression stockings, although effective, are also expensive, may be uncomfortable, require regular replacement, and have modest compliance. Not all patients who have a DVT will need to wear compression stockings, as not all patients develop PTS or indeed any sequealae resulting from their DVT. More reliable early markers of future PTS development will allow the prediction of which patients will need to wear compression stockings long term in order to prevent the development of complications of DVT and also predict those who will not need them.

The current study followed DVT patients for 5 years, using both duplex ultrasound, air plethysmography (APG), and clinical assessment to elucidate their relationship to the longer term natural history of DVT and also to determine whether any further early predictors of poor late outcomes could be found.

Section snippets

Methods

Patients with suspected acute DVT in the lower limb were assessed in our vascular laboratory. All patients with a confirmed DVT were asked to participate in this study, unless one of the following exclusion criteria applied: (1) unwillingness to participate; (2) severe immobility; (3) life expectancy <2 years; or (4) inability to travel for follow-up assessments. Written informed consent was obtained for the study, which was approved by the regional ethics committee.

Within 7–10 days after

Results

In our practice we see about 230 patients with DVT per year. For this study we assessed 122 limbs in 114 patients. The average age was 54.7 ± 16.1 years, with 66 of the patients being men (58%). The left leg was involved in 67 cases (55%), and 29 patients (25%) had a previous history of DVT in the study leg. Twenty-seven patients (24%) had an inherited thrombophilia. Sixteen patients (11%) died over the course of the study, including 10 of cancer-related causes, 2 of non–cancer-related causes,

Discussion

The pathophysiology of PTS involves a combination of valvular incompetence with reflux and venous outflow obstruction.¹² This study has broadened our understanding of the natural history of DVT by analyzing each component at regular intervals during a 5-year period.

Thrombus regression appears to be a relatively consistent process seen in all venous segments—50% in 6 months. It starts with thrombolysis as well as early in-growth of neovascular channels in the clot.¹⁸ This results in the initial

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Developing and optimizing a machine learning predictive model for post-thrombotic syndrome in a longitudinal cohort of patients with proximal deep venous thrombosis
2023, Journal of Vascular Surgery: Venous and Lymphatic Disorders
Post-thrombotic syndrome (PTS) is the most common chronic complication of deep venous thrombosis (DVT). Risk measurement and stratification of PTS are crucial for patients with DVT. This study aimed to develop predictive models of PTS using machine learning for patients with proximal DVT.
Herein, hospital inpatients from a DVT registry electronic health record database were randomly divided into a derivation and a validation set, and four predictive models were constructed using logistic regression, simple decision tree, eXtreme Gradient Boosting (XGBoost), and random forest (RF) algorithms. The presence of PTS was defined according to the Villalta scale. The areas under the receiver operating characteristic curves, decision-curve analysis, and calibration curves were applied to evaluate the performance of these models. The Shapley Additive exPlanations analysis was performed to explain the predictive models.
Among the 300 patients, 126 developed a PTS at 6 months after DVT. The RF model exhibited the best performance among the four models, with an area under the receiver operating characteristic curves of 0.891. The RF model demonstrated that Villalta score at admission, age, body mass index, and pain on calf compression were significant predictors for PTS, with accurate prediction at the individual level. The Shapley Additive exPlanations analysis suggested a nonlinear correlation between age and PTS, with two peak ages of onset at 50 and 70 years.
The current predictive model identified significant predictors and accurately predicted PTS for patients with proximal DVT. Moreover, the model demonstrated a nonlinear correlation between age and PTS, which might be valuable in risk measurement and stratification of PTS in patients with proximal DVT.
Histologic assessment of lower extremity deep vein thrombus from patients undergoing percutaneous mechanical thrombectomy
2022, Journal of Vascular Surgery: Venous and Lymphatic Disorders
Histologic analyses of deep vein thrombi (DVTs) have used autopsy samples and animal models. To the best of our knowledge, no previous study has reported on thrombus composition after percutaneous mechanical extraction. Because elements of chronicity and organization render thrombus resistant to anticoagulation and thrombolysis, a better understanding of clot evolution could inform therapy.
We performed a histologic evaluation of DVTs from consecutive patients who had undergone mechanical thrombectomy for extensive iliofemoral DVTs using the Clottriever/Flowtriever device (Inari Medical, Irvine, Calif). The DVTs were scored using a semiquantitative method according to the degree of fibrosis (collagen deposition on trichrome staining) and organization (endothelial growth with capillaries and fibroblastic penetration).
Twenty-three specimens were available for analysis, with 20 presenting as acute DVT (≤14 days from symptom onset). Of the 23 patients, 11 (48%) had had >5% fibrosis (ie, collagen deposition) and 14 (61%) had had >5% organization (ie, endothelial growth, capillaries, fibroblasts). Four patients with acute DVT had had ≥25% organized thrombus and two had had ≥25% collagen deposition. Of the 20 patients with acute DVT, 40% had had >5% fibrosis and 55% had had >5% organization. The acuity of DVT did not correlate with the amount of fibrosis or organizing scores.
A large proportion of patients with acute DVT will have histologic elements of chronicity and fibrosis. A better understanding of the relationship between such elements and the response to anticoagulant agents and fibrinolytic drugs could inform our approach to therapy.
The role of platelets in thrombus fibrosis and vessel wall remodeling after venous thrombosis
2021, Journal of Thrombosis and Haemostasis
Platelets are known to play an important role in venous thrombogenesis, but their role in thrombus maturation, resolution, and postthrombotic vein wall remodeling is unclear. The purpose of this study was to determine the role that circulating platelets play in the later phases of venous thrombosis.
We used a murine inferior vena cava (IVC) stenosis model. Baseline studies in untreated mice were performed to determine an optimal postthrombotic time point for tissue harvest that would capture both thrombus maturation/resolution and postthrombotic vein wall remodeling. This time point was found to be postoperative day 10. After undergoing IVC ultrasound on day 2 to confirm venous thrombus formation, mice were treated with a daily injection of platelet‐depleting antibody (anti‐GP1bα) to maintain thrombocytopenia or with control IgG until postoperative day 10, at which time IVC and thrombi were harvested and thrombus length, volume, fibrosis, neovascularization, and smooth muscle cell invasion analyzed. Vein wall fibrosis and intimal thickening were also determined.
Mice that were made thrombocytopenic after venous thrombogenesis had thrombi that were less fibrotic, with fewer invading smooth muscle cells. Furthermore, thrombocytopenia in the setting of venous thrombosis resulted in less postthrombotic vein wall intimal thickening. Thrombus volume did not differ between thrombocytopenic mice and their control peers.
This work suggests that circulating platelets contribute to venous thrombus maturation, fibrosis, and adverse vein wall remodeling, and that that inhibition of platelet recruitment may decrease thrombus and vein wall fibrosis, thus helping thrombolysis and preventing postthrombotic syndrome.
How i treat the postthrombotic syndrome
2018, Blood
Citation Excerpt :
Using a multidisciplinary approach, she was referred to a dermatologist and a vascular surgeon for assessment and treatment of her venous ulcer. In accordance with current guidelines42 and after discussion with the patient, anticoagulation was continued because of the unprovoked nature of her DVT and perceived low risk of bleeding. On a repeat visit to our clinic 2 months later, she reported wearing ECSs almost daily, and she lost 4 pounds and felt better overall.
The postthrombotic syndrome (PTS) is a chronic complication of deep vein thrombosis (DVT) that imposes significant morbidity, reduces quality of life, and is costly. After DVT, 20% to 50% of patients will develop PTS, and up to 5% will develop severe PTS. The principal risk factors for PTS are anatomically extensive DVT, recurrent ipsilateral DVT, obesity, and older age. By preventing the initial DVT and DVT recurrence, primary and secondary prophylaxis of DVT will reduce occurrence of PTS. The effectiveness of elastic compression stockings (ECSs) for PTS prevention is controversial. Catheter-directed thrombolysis is not effective to prevent PTS overall but may prevent more severe forms of PTS and should be reserved for select patients with extensive thrombosis, recent symptoms onset, and low bleeding risk. For patients with established PTS, the cornerstone of management is ECS, exercise, and lifestyle modifications. Surgical or endovascular interventions may be considered in refractory cases. Because of a lack of effective therapies, new approaches to preventing and treating PTS are needed. This article uses a case-based approach to discuss risk factors for PTS after DVT, how to diagnose PTS, and available means to prevent and treat PTS, with a focus on new information in the field.
Outcomes of endovascular reconstruction of the inferior vena cava with self-expanding nitinol stents
2018, Journal of Vascular Surgery: Venous and Lymphatic Disorders
Occlusion of the inferior vena cava (IVC) often causes venous claudication, leg swelling, or skin changes. We hypothesized that the outcome of nitinol stents for endovascular reconstruction of the IVC is similar to the outcome reported for steel alloy stents.
From the prospective Bern Venous Stent Registry, we investigated technical success, patency rates, and clinical outcome in consecutive patients with endovascular IVC reconstruction. During routine follow-up visits, stent patency was assessed by duplex ultrasound. Clinical outcomes were evaluated using the Bozkaya score, Villalta score, and revised Venous Clinical Severity Score.
Of the 62 patients (mean age, 46 ± 18 years), 33 (53%) patients were treated for the post-thrombotic syndrome, 17 (27%) for acute thrombosis, and 12 (19%) for nonthrombotic IVC occlusion. Technical success was achieved in 61 (98%) patients, with a mean of 4.5 ± 1.9 stents (iliac kissing stents in 84%). During follow-up (mean, 21 months), 22 (36%) underwent endovascular reintervention for symptomatic stent stenosis (13 [21%] with complete stent occlusion). Primary, primary assisted, and secondary patency rates at 24 months were 57% (95% confidence interval [CI], 50%-73%), 76% (95% CI, 65%-86%), and 87% (95% CI, 80%-95%), respectively. None developed new ulcers, and all eight patients with venous ulcers at baseline had complete healing. Twenty-nine (48%) patients showed significant clinical improvement, and another 26 (43%) were free from any symptoms or signs of venous hypertension. Patients with post-thrombotic venographic changes of the femoral veins at baseline or a history of thrombosis were more likely to lose primary patency compared with patients with normal leg inflow veins and no history of thrombosis (19 [48%] vs 3 [16%]; P = .02).
The clinical outcome of endovascular reconstruction of the IVC with nitinol stents was favorable. However, approximately one-third of the patients required reintervention to maintain stent patency, most likely because of the impaired venous inflow.
Plasminogen activator inhibitor-1 4G/5G genotype and residual venous occlusion following acute unprovoked deep vein thrombosis of the lower limb: A prospective cohort study
2017, Thrombosis Research
Citation Excerpt :
Presence of additional Factor V Leiden mutation was fairly well distributed between genotypes and therefore unlikely disturbed the results, the residual vein occlusion was not significantly different between carriers and non-carriers of Factor V Leiden Mutation. However, a previous meta-analysis of Rabinovich et al. [35] also demonstrated that genetic mutations of inherited thrombophilia have no significant influence on the risk of developing a post-thrombotic syndrome, which itself is highly dependent on the presence of residual venous obstruction on ultrasound [31,36,37]. We could not find any association between the presence of 4G allele and baseline or median plasma PAI-1 activity in individual patients over the time.
A recent study suggested that the plasminogen activator inhibitor (PAI)-1 4G/5G genotype may play a role in the resolution of deep vein thrombosis (DVT) after surgery. In the present study, we investigated the association between PAI-1 4G/5G genotype and the persistence of venous occlusion after acute idiopathic DVT of the lower limb.
The PAI-1 4G/5G genotype was determined by real-Time PCR in 43 patients with unprovoked DVT of the lower limb. Residual venous occlusion was assessed by duplex sonography 1, 3, 6, 12 and 24 months after the acute event. The PAI-1 Activity was determined by ELISA.
Ten patients (23%) were homozygous for 4G (4G/4G), 27 patients (63%) were heterozygous 4G/5G and 6 patients (14%) were homozygous for 5G (5G/5G). Residual venous occlusion (RVO) was found in 77%, 65%, 58%, 56% and 37% of the overall study population, at 1, 3, 6, 12 and 24 months after acute DVT, respectively. The presence of residual venous occlusion at 1, 3, 6, 12 and 24 months after acute unprovoked DVT did not differ significantly between genotypes, but age was associated with RVO. Plasma levels of PAI-1 activity correlated with body mass index but was not associated with genotypes in our study.
The PAI-1 4G/5G genotype was not a relevant predictor of persistent residual venous occlusion after idiopathic DVT, which however was associated with age.

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Clinical ResearchProspective Study of Natural History of Deep Vein Thrombosis: Early Predictors of Poor Late Outcomes

Background

Methods

Results

Conclusions

Introduction

Section snippets

Methods

Results

Discussion

Med Clin (Barc)

J Thromb Haemost

Eur J Vasc Surg

J Thromb Haemost

J Vasc Surg

J Vasc Surg

J Vasc Surg

Cardiovasc Surg

J Vasc Surg

J Vasc Surg

The epidemiology of venous thromboembolism in the community: implications for prevention and management

J Thromb Thrombolysis

Clinical Research
Prospective Study of Natural History of Deep Vein Thrombosis: Early Predictors of Poor Late Outcomes