Increased levels of histidine-rich glycoprotein are associated with the development of post-thrombotic syndrome.

Denser fibrin networks which are relatively resistant to lysis can predispose to post-thrombotic syndrome (PTS). Histidine-rich glycoprotein (HRG), a blood protein displaying antifibrinolytic properties, is present in fibrin clots. We investigated whether HRG may affect the risk of PTS in relation to alterations to fibrin characteristics. In venous thromboembolism (VTE) patients, we evaluated plasma HRG levels, plasma clot permeability, maximum absorbance, clot lysis time and maximum rate of increase in D-dimer levels released from clots after 3 months of the index event. We excluded patients with cancer and severe comorbidities. After 2 years of follow-up, 48 patients who developed PTS had 18.6% higher HRG at baseline. Baseline HRG positively correlated with clot lysis time, maximum absorbance, and thrombin-activatable fibrinolysis inhibitor (TAFI) activity but was inversely correlated with plasma clot permeability and maximum rate of increase in D-dimer levels released from clots. On multivariate regression model adjusted for age, fibrinogen and glucose, independent predictors of PTS were recurrent VTE, baseline HRG level, and TAFI activity. VTE recurred in 45 patients, including 30 patients with PTS, and this event showed no association with elevated HRG. Our findings suggest that increased HRG levels might contribute to the development of PTS, in part through prothrombotic fibrin clot properties.

Post-thrombotic syndrome and recurrent thromboembolism in patients with upper extremity deep vein thrombosis: A systematic review and meta-analysis.

INTRODUCTION: There is limited data on the occurrence of complications in patients with upper extremity deep vein thrombosis (UEDVT). AIMS: We aimed to determine the frequency of post-thrombotic syndrome (PTS), thrombosis recurrence and major bleeding (MB) in patients with UEDVT. MATERIAL AND METHODS: We conducted a systematic review of the literature including studies from 1970 onwards. We included observational studies, randomized trials, or cases series including >20 patients. We calculated pooled proportions using a random effects model. Subgroup analyses according to etiology and treatment modality were conducted. RESULTS: A total of 62 studies comprising 3550 patients were included. The pooled proportions for PTS and recurrence were 19.4% (95% CI 11.3-27.6) and 7.5% (95% CI 4.1-10.9), respectively. With a mean follow up of 6 months, the proportion of PTS was higher in patients with primary (unprovoked) UEDVT compared to secondary, whereas recurrence was higher in secondary UEDVT. PTS was more frequent in patients treated with anticoagulation alone compared to thrombolysis or surgical decompression. The pooled proportion for MB was 5.0% (95% CI 0.3-9.7) after anticoagulation alone and 3.8% (95% CI: 2.4-5.8%) after thrombolysis and/or surgery. CONCLUSIONS: This study suggests that UEDVT is associated with significant rates of PTS and recurrence and its treatment has a relatively low risk of major bleeding. Differences exist depending on etiology and treatment modality.

Pre-Clinical Model to Study Recurrent Venous Thrombosis in the Inferior Vena Cava.

BACKGROUND: Patients undergoing deep vein thrombosis (VT) have over 30% recurrence, directly increasing their risk of post-thrombotic syndrome. Current murine models of inferior vena cava (IVC) VT model host one thrombosis event. OBJECTIVE: We aimed to develop a murine model to study IVC recurrent VT in mice. MATERIALS AND METHODS: An initial VT was induced using the electrolytic IVC model (EIM) with constant blood flow. This approach takes advantage of the restored vein lumen 21 days after a single VT event in the EIM demonstrated by ultrasound. We then induced a second VT 21 days later, using either EIM or an IVC ligation model for comparison. The control groups were a sham surgery and, 21 days later, either EIM or IVC ligation. IVC wall and thrombus were harvested 2 days after the second insult and analysed for IVC and thrombus size, gene expression of fibrotic markers, histology for collagen and Western blot for citrullinated histone 3 (Cit-H3) and fibrin. RESULTS: Ultrasound confirmed the first VT and its progressive resolution with an anatomical channel allowing room for the second thrombus by day 21. As compared with a primary VT, recurrent VT has heavier walls with significant up-regulation of transforming growth factor-ß (TGF-ß), elastin, interleukin (IL)-6, matrix metallopeptidase 9 (MMP9), MMP2 and a thrombus with high citrullinated histone-3 and fibrin content. CONCLUSION: Experimental recurrent thrombi are structurally and compositionally different from the primary VT, with a greater pro-fibrotic remodelling vein wall profile. This work provides a VT recurrence IVC model that will help to improve the current understanding of the biological mechanisms and directed treatment of recurrent VT.

Postthrombotic Syndrome in Patients Treated With Rivaroxaban or Warfarin for Venous Thromboembolism.

Postthrombotic syndrome (PTS) is a frequent complication of venous thromboembolism (VTE). Using MarketScan claims data from January 2012 to June 2015, we identified adults with a primary diagnosis code for VTE during a hospitalization/emergency department visit, ≥6 months of insurance coverage prior to the index event and newly started on rivaroxaban or warfarin within 30 days of the index VTE. Patients with <4-month follow-up postindex event or a claim for any anticoagulant during 6-month baseline period were excluded. Differences in baseline characteristics between rivaroxaban and warfarin users were adjusted for using inverse probability of treatment weights based on propensity scores. Patients were followed for the development of PTS starting 3 months after the index VTE. Cox regression was performed and reported as hazard ratios with 95% confidence intervals (CIs). In total, 10 463 rivaroxaban and 26 494 warfarin users were followed for a mean of 16 ± 9 (range, 4-39) months. Duration of anticoagulation was similar between cohorts (median = 6 months). Rivaroxaban was associated with a 23% (95% CI: 16-30) reduced hazard of PTS versus warfarin. Rivaroxaban was associated with a significant risk reduction in symptoms of PTS compared to warfarin in patients with VTE treated in routine practice.

Diagnostic scales for the post-thrombotic syndrome.

Post-thrombotic syndrome (PTS) is the most common long-term complication after deep vein thrombosis (DVT) developing in up to 70% of the patients. PTS is diagnosed on the basis of typical symptoms and signs of the lower limb with a previous DVT, but no objective diagnostic test exists. A number of diagnostic scales have been developed primarily for research purposes. An optimal diagnostic test for PTS should be reliable and easy to use, sensitive and specific, able to grade PTS severity, and to identify changes over time. We have identified reports on seven diagnostic scales that have been used for the diagnosis of PTS; the Widmer classification, the Clinical-Etiological-Anatomical-Pathological (CEAP) classification, the Venous Clinical Severity Score (VCSS), the Brandjes scale, the Ginsberg measure, the Villalta scale, and the Patient-reported Villalta scale. The aim of this paper was to review and present the existing diagnostic scales for PTS in adults and their utility in clinical studies.

Post-thrombotic syndrome in children.

The post-thrombotic syndrome (PTS) is the most common long-term complication of pediatric deep venous thrombosis (DVT). It is a burdensome condition that can lead to severe disability and poor quality-of-life of affected children. Although its pathophysiology remains poorly understood, it is thought to be the result of chronic venous hypertension. Recent studies have shown that the inflammatory response associated with an acute DVT likely plays a key role in the development of PTS. The Manco-Johnson Instrument and the modified Villalta Scale are the most widely used instruments for the diagnosis of pediatric PTS. To date, few prognostic indicators for the development of PTS following pediatric-onset DVT have been identified and substantiated in published research, limiting our ability to identify those patients at high-risk for the development of this complication. There is also limited evidence on therapeutic strategies and long-term outcomes of pediatric PTS. Further research aimed at improving our understanding of the pathophysiology and prognostic indicators of PTS is needed to enhance the currently limited risk prediction models for pediatric PTS. Early identification of pediatric patients at risk for PTS is essential to investigate preventive and therapeutic interventions aimed at decreasing the risk and severity of this complication in children. This review aims to summarize the current available evidence on the pathophysiology, risk factors, diagnosis, and management of pediatric PTS.

Prevention and treatment of the post-thrombotic syndrome.

Post-thrombotic syndrome (PTS) is a complication that develops in up to 50% of patients with deep vein thrombosis (DVT) and manifests as symptoms and signs of chronic venous insufficiency of varying severity. PTS negatively affects patient's quality of life and causes significant burden to the healthcare system. The risk for PTS development can be markedly reduced by preventing DVT and providing appropriate anticoagulation once it develops. Patients with extensive proximal (iliofemoral) DVT may benefit from invasive interventions, such as catheter-directed thrombolysis. The effectiveness of elastic compression stockings (ECS) for PTS prevention has not been conclusively demonstrated in randomized trials. Treatment of PTS is primarily based on ECS, exercise and lifestyle modifications. The effectiveness of various pharmacologic agents for PTS treatment remains controversial. Surgical or radiological interventions for vein reconstruction or revascularization may be considered in refractory cases. This review summarizes current evidence regarding prevention and treatment of PTS of the lower limbs in adults.

Thrombectomy and thrombolysis for the prevention and treatment of postthrombotic syndrome.

Postthrombotic syndrome (PTS) is a frequent complication of lower-extremity deep vein thrombosis (DVT), occurring in approximately 40% of patients despite the use of anticoagulant therapy. PTS causes significant impairment of patients' health-related quality of life, and no evidence-based therapies have been consistently effective. Catheter-directed thrombolysis and thrombectomy have been shown to remove acute thrombus, and it has been hypothesized they could prevent or reduce PTS. However, because these procedures can be associated with complications, mainly bleeding, randomized trial data are needed to determine when they should be used. In this article, I summarize the current status of thrombus removal procedures for DVT to provide contemporary guidance to clinicians seeking to individualize treatment decisions for their patients.

The importance of post thrombotic syndrome as an outcome after deep venous thrombosis: A survey of Canadian thrombosis clinicians.

OBJECTIVES: The development of post thrombotic syndrome (PTS) is a major source of morbidity and reduced quality of life. We sought to determine the value assigned by clinicians to post thrombotic syndrome and whether clinicians believe that any post thrombotic syndrome or severe post thrombotic syndrome are important outcomes to assess after deep vein thrombosis (DVT) as compared to other outcomes. DESIGN: The design of the study was a self-responded electronic survey. Questions for the online survey were designed by two authors (R.I. and E.G.). METHODS: The survey was distributed to 233 members of Thrombosis Canada and the Canadian Society for Vascular Surgery between August 2014 and October 2014. RESULTS: There were 84 responses to the survey with complete responses were obtained from 71 respondents for a response rate of 36%. PTS was ranked as a significantly less important outcome after DVT than recurrent DVT, pulmonary embolism during treatment, major bleeding, death, quality of life, venous ulceration and severe post thrombotic syndrome (all comparisons p<0.05 by two sample t-test). CONCLUSIONS: Our survey determined that "any post thrombotic syndrome" is perceived by physicians as less important than other DVT outcomes. Thus, "Severe PTS" and not "Any PTS" should be included as an outcome measure in studies investigating acute DVT.

[Endovascular treatment of a patient with post-thrombotic disease and obstruction of a cava filter]. / Éndovaskuliarnoe lechenie bol'nogo s posttromboticheskoi bolezn'iu i obstruktsiei kava-fil'tra.

Balloon angioplasty and stenting have increasingly been gaining widespread application for treatment of post-thrombotic alterations in the system of the vena cava. Endovascular ultrasonographic examination makes it possible with the utmost degree of reliability to determine both the extension and degree of the narrowing of venous segments, thus proving a possibility of choosing a venous stent of an appropriate diameter. Restoration of an adequate venous lumen leads to normalization of blood flow and elimination of venous hypertension. However, unsolved as yet remains the problem concerning proper management of post-thrombotic obstructions of the inferior vena cava at the level of a cava filter. Owing to a wide variety of configurations of cava filters to deploy, there are no common approaches to elimination of such obstruction. Presented herein is a clinical case report regarding successful endovascular treatment of a patient diagnosed with post-thrombotic disease secondary to endured thrombosis. The findings of both phlebography and endovascular ultrasonographic examination made it possible to diagnose obstruction of the left common iliac vein, external iliac vein, and inferior vena cava to the level of the cava filter previously deployed. In the segment of the inferior vena cava at the level of the cava filter also revealed was a pronounced luminal narrowing exceeding 90% of its diameter. We carried out stenting of the common and external iliac veins, inferior vena cava, and the cava filter. Swelling of the left leg subsided spontaneously within 2 weeks and the first postoperative month was accompanied by gradual disappearance of the previously existing feeling of heaviness in the lower limbs and a dramatic decrease in fatigue by the end of the working day.

Vein wall remodeling in patients with acute deep vein thrombosis and chronic postthrombotic changes.

Essentials This study examined vein wall remodeling in acute thrombosis and postthrombotic syndrome (PTS). Thrombus-wall interface was measured using ultrasound real-time high definition zoom. Experimental cohorts demonstrated increased vein wall thickness localized to affected segments. Presence of thrombus or PTS are the most important factors affecting wall thickening. SUMMARY: Introduction A few studies have investigated venous wall remodeling after venous thrombosis by using rodent models. Such information is lacking in humans. This study was designed to determine the acute and chronic effects of thrombus on the vein wall. Methods Patients aged > 16 years with deep vein thrombosis diagnosed by duplex ultrasound were assessed by the use of case-control methodology. Those with recurring thrombotic episodes, cardiorespiratory disease, terminal cancer, morbid obesity, penetrating trauma or significant inflammation were excluded. High-resolution ultrasound was employed to determine wall thickness, with strict quality criteria and inclusion of only technically adequate ultrasound images. Results Data were collected from patients with acute thrombosis (35), patients with chronic postthrombotic changes (15), and unaffected controls (32), with 853 total vein segments being analyzed. As compared with controls (mean 0.37 mm; 95% confidence interval [CI] 0.37-0.38 mm), venous wall thickness was increased in acute (mean 0.63 mm; 95% CI 0.61-0.64 mm) and postthrombotic (mean 0.85 mm; 95% CI 0.80-0.91 mm) venous segments. Ipsilateral, contralateral and unaffected control vein segments were not different. Ipsilateral segments were thicker than controls in postthrombotic syndrome (PTS) patients, but not in acute patients. Multiple regression analyses demonstrated small impacts of age and sex on vein wall thickness. Conclusions Wall thickness increases in all lower-tcglimb venous segments of patients with acute and postthrombotic disease. Age and sex may affect wall thickness, although further investigation is required to clarify their impact. The equivalence of ipsilateral and unaffected control segments suggests that acute vein wall remodeling is mediated through direct interaction with the thrombus, whereas remodeling in PTS patients may be affected by other factors.

Rivaroxaban versus warfarin in the prevention of post-thrombotic syndrome.

INTRODUCTION: Post-thrombotic syndrome (PTS) is a chronic complication of deep vein thrombosis (DVT) that affects 20% to 50% of DVT patients. Standard DVT treatment included vitamin K antagonists (usually warfarin) with low-molecular-weight heparin in the initial period. In recent years, direct oral anticoagulants (DOAC) were introduced. We aimed to investigate the influence of rivaroxaban and warfarin on PTS development. METHODS: Consecutive patients treated for DVT were included, 39 were treated with warfarin and 61 with rivaroxaban. We assessed symptoms and signs of PTS and calculated Villalta score 23months (median) after acute DVT diagnosis. Differences between patients treated with rivaroxaban and warfarin were investigated. RESULTS: Patients in the rivaroxaban group had a lower prevalence of PTS than those treated with warfarin (25% vs. 49%, p=0.013). Logistic regression showed odds ratio of 2.9 (1.2-6.8, p=0.014) for PTS development in warfarin group compared to rivaroxaban group. When adjusted for other variables, the odds ratio was 3.5 (1.1-11.0, p=0.035). CONCLUSIONS: Treatment of DVT with rivaroxaban might be associated with a lower risk for PTS development. A larger randomized trial would be needed for stronger evidence.

Scoring Systems for Postthrombotic Syndrome.

Postthrombotic syndrome (PTS) is the most common long-term complication after deep vein thrombosis (DVT) and is associated with reduced quality of life. There is no single objective test to diagnose the presence of PTS and it is usually diagnosed on the basis of typical symptoms and signs in a limb previously affected by DVT. Scoring systems for PTS are primarily developed as research tools, but could possibly also be useful in the clinical setting. A main advantage of a good scoring system is standardization of the diagnostic process. An optimal scoring system should be both sensitive and specific for PTS, but this has been difficult to achieve because the symptoms and signs of PTS can be similar to other conditions leading to complaints in the lower limb. In an effort to standardize the definition of PTS, in 2009, the International Society on Thrombosis and Haemostasis Subcommittee on Control of Anticoagulation reviewed available scales and recommended use of the Villalta scale as the most appropriate measure to diagnose and grade the severity of PTS. The aim of this article is to review the existing scoring systems for PTS and to present our view on the advantages and disadvantages of these diagnostic tools.

Post Thrombotic Syndrome.

Venous insufficiency following deep venous thrombosis is known as the post thrombotic syndrome. Whilst its presentation and symptoms can vary slightly between individuals, it can have a profound effect on quality of life. Symptoms range from mild limb swelling to severe intractable ulceration. A number of scoring systems have been developed to help monitor the disease progression, response to treatment as well as to classify patients for research purposes.Treatment involves a combination of therapies, including compression stockings, venous stenting for out flow obstruction and in some instances deep venous bypass. A considerable effort is made in preventing post thrombotic syndrome with a number of trials looking into the effect of prompt and stable anticoagulation, the effect of compression stockings, the effect of exercise and the outcomes following early thrombus removal strategies such as catheter directed and pharmacomechanical thrombolysis.

Stenting for chronic obstructive venous disease: A current comprehensive meta-analysis and systematic review.

OBJECTIVES: The aim of this article was to summarize the efficacy and safety of venous stents in chronic obstructive venous disease (COVD) including postthrombotic syndrome (PTS) and nonthrombotic iliac vein lesions (NIVL). METHODS: We searched PubMed for case series (prospective and retrospective) that focused on venous stents in the treatment of COVD published between 1st January, 2000 and 15th July, 2014. Then, we analyzed the perioperative complications, subsequent antithrombotic treatment, clinical outcomes, and long-term patency of this procedure. RESULTS: Overall, 1987 patients from 14 studies were included in our study. The incidence of the 30-day thrombotic events was 2.0% (4.0% in PTS vs. 0.8% in NIVL, p = 0.0002). The rates of access site complications and stent migration were 1.7% and 1.3%, respectively. The incidence of retroperitoneal bleeding and contrast extravasation was 1.8%. Back pain was more common with a rate of 62.9%. With stent placement, there was a significant pain and edema relief in COVD patients and the clinical-etiology-anatomy-pathophysiology scores declined. The rate of ulcer healing was 72.1% (70.3% in PTS vs. 86.9% in NIVL, p = 0.0022), and the ulcer recurrence rate was 8.7%. The primary, assisted primary, and secondary patency rates were 91.4%, 95.0%, and 97.8%, respectively, at 12 months and 77.1%, 92.3%, and 94.3%, respectively, at 36 months; however, the patency rates in PTS were lower than those in NIVL. CONCLUSIONS: Stents may be a relatively effective and safe approach for PTS and NIVL patients because of the low incidence of perioperative complications and satisfying long-term patency. Some outcomes of stents in NIVL patients may be better than those in PTS patients.

Combination of factor Xa inhibition and antiplatelet therapy after stenting in patients with iliofemoral post-thrombotic venous obstruction.

OBJECTIVES: Studies addressing optimal postprocedural pharmacological management after endovascular stenting of iliofemoral post-thrombotic venous obstruction are lacking. We report our early clinical experience with a combination of rivaroxaban and clopidogrel in patients after iliofemoral post-thrombotic venous obstruction stenting. METHODS: Demographic, procedural, and follow-up data of nine patients (seven women; mean age of 32 ± 11 years) undergoing 10 procedures for iliofemoral post-thrombotic venous obstruction performed between August 2012 and January 2014 were retrospectively reviewed. After endovascular intervention, all patients were administered 20 mg rivaroxaban once daily (s.i.d.) and 75 mg clopidogrel s.i.d. or every second day depending on the individual drug responsiveness for at least six months. The adenosine diphosphate-induced platelet aggregation (platelet aggregation, in aggregation units × min) was assessed on a Multiplate analyzer. Patency was verified venographically at procedure end and was evaluated with duplex ultrasound in regular follow-ups. RESULTS: Iliofemoral venous flow was successfully re-established by percutaneous endovascular angioplasty and stent implantation in nine left-sided and one bilateral iliofemoral post-thrombotic venous obstruction. Under dual treatment strategy of rivaroxaban and clopidogrel with platelet aggregation control (median (range): 285 aggregation units × min (192; 402)), none of the patients experienced restenosis or stent thrombosis, respectively. After a median follow-up of 14 months (range: 6-26 months), the primary patency rate was 100% and no in-stent restenosis, stent occlusion or relevant minor or major bleeding occurred. CONCLUSION: Combined factor Xa inhibition and tailored antiplatelet therapy after stenting of iliofemoral post-thrombotic venous obstruction were safe and performed favorably in terms of vessel patency.

Clot structure and fibrinolytic potential in patients with post thrombotic syndrome.

INTRODUCTION: Post-thrombotic syndrome (PTS) is a chronic sequel of deep vein thrombosis (DVT). The clot structure and fibrinolytic potential in PTS is currently unknown. OBJECTIVE: To assess the fibrinolytic potential and clot structure in patients with PTS. MATERIALS AND METHODS: Patients with a history of DVT were included in a case-control study: patients with PTS (cases n=30) and without PTS (controls n=30), and 30 apparently healthy individuals (HI) without venous thromboembolism (VTE) or venous insufficiency were enrolled. Fibrinolysis and clot structure were assessed by turbidimetric assays, permeation, and confocal microscopy. Fibrinogen was measured by Clauss and fibrinogen γ' by ELISA. RESULTS: We observed a significant trend of decreasing maximum turbidity from HI (median 0.52 [IQR 0.46-0.62]), to controls (0.49 [IQR 0.41-0.55]), to cases (0.46 [IQR 0.39-0.49]) p=0.020. Fibrinogen was lower in patients (cases and controls) (3.69g/L [IQR 3.31-4.26]) compared to HI (4.17 [IQR 3.69-4.65]) p=0.041. Patients with recurrent VTE had lower maximum turbidity and lower permeation than patients with one episode of VTE; (0.31 [IQR 0.25-0.39] versus 0.38 [IQR 0.34-0.44] p=0.008) and (6.0×10(-9)/cm(2) [IQR 5.1-7.9] versus 7.7×10(-9)/cm(2) [IQR 6.0-10.0] p=0.047) respectively, at equal fibrinogen levels. There were no differences in lysis time, confocal microscopy, or fibrinogen γ'. CONCLUSIONS: Lower maximum turbidity, indicating a tendency towards thinner fibres and denser clots, was found in patients with PTS as well as in patients with recurrent VTE. Fibrinogen levels did not explain these differences in clot structure. The abnormal clot structure may contribute to the increased thrombotic risk profile in patients with PTS.

A histological and functional description of the tissue causing chronic postthrombotic venous obstruction.

BACKGROUND: Postthrombotic intraluminal tissue causing postthrombotic syndrome (PTS) has not been well described. This study defines its histological characteristics and assess whether tissue function evolves over time. METHODS: Specimens from 18 common femoral veins (CFV) from 16 patients obtained during CFV endovenectomy and iliocaval recanalization were examined. Phase 1 used hematoxylin and eosin and Masson's trichrome stains for collagen, immunohistochemical, and Von Kossa stains. Phase 2 examined young (≤ one year) and mature (≥10years from acute DVT) specimens to evaluate evolution of endothelial function. Antibodies to four biomarkers were used to examine specific functions of endothelial cells lining neovessels and recanalization channels (RC). RESULTS: Phase 1: Specimens demonstrated 80-90% of collagen type I, 10-20% of collagen type III, and dystrophic calcification. Neovessels and RC were in close proximity to each other. Thrombus and smooth muscle cells were absent, but white blood cells were present. Phase 2: VEGFR2 receptor uptake was more abundant in neovessels than RC and more prominent in younger specimens. Neovascular, nonchannel cells were observed more frequently in young specimens. CD-31 was similar in young and mature specimens. TIE-2 and von Willebrand factor antibodies had greater uptake in mature specimens. CONCLUSION: Tissue causing chronic postthrombotic venous obstruction is predominantly type I collagen. Neovascularization and recanalization occur in close proximity. The biomarker for neovascularization and angiogenesis (VEGFR2) was more prominent in young specimens whereas TIE-2, a stabilizing biomarker and vWF were more frequently observed in mature specimens.