Predictors of Early Mortality in Cancer-Associated Thrombosis: Analysis of the RIETE Database.

Cancer-associated thrombosis (CT) carries a high, heterogeneous, and poorly predicted likelihood of mortality. Thus, we aimed to define predictors of 30-day mortality in 10,025 patients with CT. In a randomly selected derivation cohort, we used recursive partitioning analysis to detect variables that select for a risk of mortality within 30 days. In a validation cohort, we evaluated our results using Cochran-Armitage test. The most common types of cancer were lung (16%), breast (14%), and colorectal (14%); median age was 69 years (range, 14-101); most had metastatic disease (63%); 13% of patients died within 30 days. In the derivation cohort ( n = 6,660), a white blood cell (WBC) count in the highest quartile predicted early mortality (odds ratio, 7.8; 95% confidence interval [CI], 4.6-13.1); and the presence of metastatic disease, pulmonary embolism (PE), and immobility defined the risk of those with normal WBC count. We defined death risk according four sequential questions: (1) Does the patient have an elevated WBC count? (Yes, group D). (2) If no, does the patient have metastasis? (No, group A). (3) If yes, is the patient immobile? (Yes, group D). (4) If no, does the patient have a PE? (Yes, group C; no, group B). In the validation cohort ( n = 3,365), the 30-day risk of death was 2.9% in group A (95% CI, 1.9-4.3), compared with 25% in group D (95% CI, 22.5-27.5), and there was a rate escalation between groups ( p for trend < 0.01). In conclusion, with four sequential questions, the risk of death in CT can be easily stratified. An elevated WBC count at baseline predicted 30-day mortality better than metastases, PE, or immobility.

Outcome after discontinuing anticoagulant therapy in women with venous thromboembolism during hormonal use.

INTRODUCTION: Whether women developing venous thromboembolism (VTE) while using hormonal therapy should be classified as having "unprovoked" or "provoked" VTE is controversial. METHODS: We used the RIETE (Registro Informatizado Enfermedad TromboEmbólica) database to compare the rate of symptomatic VTE recurrences after discontinuing anticoagulation in 3 subgroups of women aged ≤50years without cancer, pregnancy or puerperium: (1) those with hormonal therapy and no additional risk factors (hormonal users only); (2) those with unprovoked VTE; and (3) those with additional risk factors, with or without hormonal therapy. RESULTS: As of March 2016, 1513 women had been followed-up for at least one month after discontinuing anticoagulation. Of these, 654 (43%) were hormonal users only, 390 (26%) had unprovoked VTE and 469 (31%) had transient risk factors with or without hormonal therapy. After discontinuing anticoagulation, the rate of VTE recurrences in women with hormonal use only (2.44 per 100 patient-years; 95% CI: 1.53-3.69) was significantly lower than in those with unprovoked VTE (6.03; 95% CI: 3.97-8.77) and similar to those with transient risk factors (2.58; 95% CI: 1.50-4.13). Interestingly, the rate of VTE recurrences presenting as pulmonary embolism in women with hormonal use only (0.55 per 100 patient-years; 95% CI: 0.18-1.29) was similar to those with transient risk factors (0.46; 95% CI: 0.09-1.33) and 4-fold lower than in women with unprovoked VTE (2.23; 95% CI: 1.07-4.10). CONCLUSIONS: After discontinuing anticoagulation, the rate of VTE recurrences in hormonal users only was significantly lower than in women with unprovoked VTE and similar to the rate in women with additional risk factors.

Clinical Prognosis of Nonmassive Central and Noncentral Pulmonary Embolism: A Registry-Based Cohort Study.

BACKGROUND: Whether the localization of nonmassive pulmonary embolism (PE) is associated with the short-term and long-term prognosis of patients remains unknown. Our aim was to characterize associations of nonmassive PE localization with risks of recurrent VTE, major bleeding, and mortality during and after anticoagulation. METHODS: Among participants of the Registro Informatizado de la Enfermedad ThromboEmbòlica (RIETE) registry with incident symptomatic nonmassive PE diagnosed by CT scan, we compared risks of recurrent VTE, major bleeding, and mortality during and after anticoagulation between central PE (main pulmonary artery) and noncentral PE (more peripheral arteries) using Cox proportional hazard-adjusted models. RESULTS: Of the 6,674 participants, patients with central PE (40.5%) had age (mean 66 years), sex (46.9% male sex), and proportion of idiopathic (45.0%) and cancer-related (22.3%) PE that were similar to those of patients with noncentral PE. During anticoagulation (5,256.1 patient-years), the risk of recurrent VTE was similar between the two groups (2.5 vs 2.1 per 100 patient-years; adjusted hazard ratio [aHR], 1.32; 95% CI, 0.91-1.90), as were risks of major bleeding and mortality. After anticoagulation was discontinued (2,175.4 patient-years), participants with central PE had a borderline greater risk of recurrent VTE than did participants with noncentral PE (11.0 vs 8.0 per 100 patient-years; aHR, 1.34; 95% CI, 1.01-1.78) but not when restricted to participants after unprovoked PE (13.8 vs 11.9 per 100 patient-years; aHR, 1.15; 95% CI, 0.79-1.68; P = .48). Risks of major bleeding and mortality were similar. CONCLUSIONS: In nonmassive PE, central localization of PE is associated with greater risk of recurrent VTE after anticoagulation cessation. However, the low magnitude of this association and the absence of association after unprovoked PE suggest that the clinical relevance of this finding is limited and that the duration of anticoagulation should not be tailored to PE localization after nonmassive unprovoked PE.

Clinical history and antithrombotic treatment of incidentally detected splanchnic vein thrombosis: a multicentre, international prospective registry.

BACKGROUND: Little information is available about the clinical history of patients with incidentally detected splanchnic vein thrombosis and its therapeutic management remains controversial. The aim of this study was to assess the risk factors, therapeutic strategies, and long-term outcomes of incidentally detected splanchnic vein thrombosis. METHODS: We analysed data from patients with incidentally detected splanchnic vein thrombosis who were enrolled in an international, multicentre, prospective cohort study of splanchnic vein thrombosis between 2008 and 2012. The study was done at 31 centres in 11 countries (Italy, South Korea, Germany, Canada, Belgium, the Netherlands, Brazil, USA, France, Israel, UK). Information about demographic characteristics, risk factors, and treatment was collected. The study outcomes during the 2-year follow-up were major bleeding (International Society on Thrombosis and Haemostasis definition plus the need for hospital admission), thrombotic events (venous or arterial thromboses), and mortality. The primary analysis period was from the diagnosis of incidentally detected splanchnic vein thrombosis until the first adjudicated clinical outcome or the end of follow-up. FINDINGS: Between May 2, 2008, and Jan 30, 2012, we enrolled 177 patients with incidentally detected splanchnic vein thrombosis (median age 57 years [IQR 49-66], 118 [67%] men, 138 [78%] patients with portal vein thrombosis). The most common underlying diseases were liver cirrhosis (82 [46%] patients) and solid cancer (62 [35%] patients). Anticoagulant treatment was prescribed to 109 (62%) patients. Median duration of anticoagulation was 6 months (IQR 5-12) for patients who received parenteral anticoagulants alone and 24 months (IQR 12-24) for patients treated with vitamin K antagonists. During a median follow-up of 2 years (IQR 1-2), the incidence of major bleeding was 3·3 events (95% CI 1·7-6·3) per 100 patient-years and the incidence of thrombotic events was 8·0 events (95% CI 5·2-12·1) per 100 patient-years. On-treatment incidence was 3·2 events (95% CI 1·2-8·4) per 100 patient-years for major bleeding and 3·9 events (95% CI 1·6-9·5) per 100 patient-years for thrombotic events. In multivariate analysis, anticoagulant treatment as a time-dependent variable reduced the incidence of thrombotic events (hazard ratio 0·85, 95% CI 0·76-0·96) without increasing the risk of major bleeding (p>0·05). In patients with clinically suspected splanchnic vein thrombosis, the incidence of major bleeding was 3·9 events (95% CI 2·6-5·7) per 100 patient-years and the incidence of thrombotic events was 7·0 events (95% CI 5·2-9·3) per 100 patient-years. INTERPRETATION: Our results show that the prognosis of incidentally detected splanchnic vein thrombosis is similar to that of clinically suspected splanchnic vein thrombosis and suggest that similar treatment strategies should be applied. FUNDING: Pfizer Canada research grant.

Long-term Clinical Outcomes of Splanchnic Vein Thrombosis: Results of an International Registry.

IMPORTANCE: Little information is available on the long-term clinical outcome of patients with splanchnic vein thrombosis (SVT). OBJECTIVE: To assess the incidence rates of bleeding, thrombotic events, and mortality in a large international cohort of patients with SVT. DESIGN, SETTING, AND PARTICIPANTS: A prospective cohort study was conducted beginning May 2, 2008, and completed January 30, 2014, at hospital-based centers specialized in the management of thromboembolic disorders; a 2-year follow-up period was completed January 30, 2014, and data analysis was conducted from July 1, 2014, to February 28, 2015. Participants included 604 consecutive patients with objectively diagnosed SVT; there were no exclusion critieria. Information was gathered on baseline characteristics, risk factors, and antithrombotic treatment. Clinical outcomes during the follow-up period were documented and reviewed by a central adjudication committee. MAIN OUTCOMES AND MEASURES: Major bleeding, defined according to the International Society on Thrombosis and Hemostasis; bleeding requiring hospitalization; thrombotic events, including venous and arterial thrombosis; and all-cause mortality. RESULTS: Of the 604 patients (median age, 54 years; 62.6% males), 21 (3.5%) did not complete follow-up. The most common risk factors for SVT were liver cirrhosis (167 of 600 patients [27.8%]) and solid cancer (136 of 600 [22.7%]); the most common sites of thrombosis were the portal vein (465 of 604 [77.0%]) and the mesenteric veins (266 of 604 [44.0%]). Anticoagulation was administered to 465 patients in the entire cohort (77.0%) with a mean duration of 13.9 months; 175 of the anticoagulant group (37.6%) received parenteral treatment only, and 290 patients (62.4%) were receiving vitamin K antagonists. The incidence rates (reported with 95% CIs) were 3.8 per 100 patient-years (2.7-5.2) for major bleeding, 7.3 per 100 patient-years (5.8-9.3) for thrombotic events, and 10.3 per 100 patient-years (8.5-12.5) for all-cause mortality. During anticoagulant treatment, these rates were 3.9 per 100 patient-years (2.6-6.0) for major bleeding and 5.6 per 100 patient-years (3.9-8.0) for thrombotic events. After treatment discontinuation, rates were 1.0 per 100 patient-years (0.3-4.2) and 10.5 per 100 patient-years (6.8-16.3), respectively. The highest rates of major bleeding and thrombotic events during the whole study period were observed in patients with cirrhosis (10.0 per 100 patient-years [6.6-15.1] and 11.3 per 100 patient-years [7.7-16.8], respectively); the lowest rates were in patients with SVT secondary to transient risk factors (0.5 per 100 patient-years [0.1-3.7] and 3.2 per 100 patient-years [1.4-7.0], respectively). CONCLUSIONS AND RELEVANCE: Most patients with SVT have a substantial long-term risk of thrombotic events. In patients with cirrhosis, this risk must be balanced against a similarly high risk of major bleeding. Anticoagulant treatment appears to be safe and effective in most patients with SVT.

Clonal populations of hematopoietic cells with paroxysmal nocturnal hemoglobinuria phenotype in patients with splanchnic vein thrombosis.

INTRODUCTION: Splanchnic vein thrombosis (SVT) is a serious complication in patients with paroxysmal nocturnal hemoglobinuria (PNH). Mutant PNH clones can be associated with an increased risk of SVT even in the absence of overt disease, but their prevalence in non-selected SVT patients remains unknown. MATERIALS AND METHODS: Patients with objective diagnosis of SVT and without known PNH were tested for the presence of PNH clone using high-sensitivity flow cytometric analysis. RESULTS: A total of 202 SVT patients were eligible, 58.4% were males, mean age was 54.6years (range 17-94), site of thrombosis was portal in 103 patients, mesenteric in 67, splenic in 37, and supra-hepatic in 10. SVT was associated with JAK2 V6167F in 28 of 126 (22.2%) screened patients, liver cirrhosis in 15.3% patients, recent surgery in 10.9%, and myeloproliferative neoplasm in 10.6%, whereas in 34.6% of patients neither permanent nor transient risk factors were detected. None of the patients had a clearly demonstrable PNH clone, but in two patients (0.99%, 95% CI 0.17-3.91) we observed very small PNH clones (size 0.014% and 0.16%) confirmed in two independent samples. One patient had portal vein thrombosis and no associated risk factors, the second had superior mesenteric vein thrombosis and inflammatory bowel disease. CONCLUSIONS: Very small PNH clones can be detected in patients with SVT and no clinical manifestations of disease. Future studies are needed to explore the potential role of this finding in the pathogenesis of SVT.

D-dimer levels and 90-day outcome in patients with acute pulmonary embolism with or without cancer.

BACKGROUND: The prognostic value of D-dimer testing in patients with acute pulmonary embolism (PE) has not been thoroughly studied. METHODS: We used the RIETE Registry data to assess the 90-day prognostic value of increased IL Test D-dimer levels at baseline in patients with PE, according to the presence or absence of cancer. RESULTS: As of May 2013, 3,283 patients with acute PE underwent D-dimer testing using IL Test D-dimer. Among 2,588 patients without cancer, those with D-dimer levels in the highest quartile had a higher rate of fatal PE (2.6% vs. 0.9%; p=0.002), fatal bleeding (1.1% vs. 0.3%; p=0.017) and all-cause death (9.1% vs. 4.4%; p<0.001) at 90 days compared with those with levels in the lowest quartiles. Among 695 patients with cancer, those with levels in the highest quartile had a similar rate of fatal PE or fatal bleeding but higher mortality (35% vs. 24%; p<0.01). On multivariate analysis, non-cancer patients with D-dimer levels in the highest quartile had an increased risk for fatal PE (odds ratio [OR]: 3.3; 95% CI: 1.6-6.6), fatal bleeding (OR: 4.3; 95% CI: 1.4-13.7) and all-cause death (OR: 2.1; 95% CI: 1.4-3.1) compared with patients with levels in the lowest quartiles. CONCLUSIONS: Non-cancer patients with acute PE and IL Test D-dimer levels in the highest quartile had an independently higher risk for fatal PE, fatal bleeding and all-cause death at 90 days than those with levels in the lowest quartiles. In patients with cancer, D-dimer levels failed to predict fatal PE or fatal bleeding.

Interventional treatment of venous thromboembolism: a review.

Venous thromboembolism (VTE), including deep vein thrombosis (DVT) and pulmonary embolism (PE), is the third most common cardiovascular disease after coronary artery disease and cerebrovascular disease and is responsible for significant morbidity and mortality in the general population. Full dose anticoagulation is the standard therapy for VTE, both for the acute and the long-term phase. The latest guidelines of the American College of Chest Physicians recommend treatment with a full-dose of unfractioned heparin (UFH), low-molecular-weight-heparin (LMWH), fondaparinux, vitamin K antagonist (VKA) or thrombolysis for most patients with objectively confirmed VTE. Catheter-guided thrombolysis and trombosuction are interventional approaches that should be used only in selected populations; interruption of the inferior vena cava (IVC) with a filter can be performed to prevent life-threatening PE in patients with VTE and contraindications to anticoagulant treatment, bleeding complications during antithrombotic treatment, or VTE recurrences despite optimal anticoagulation. In this review we summarize the currently available literature regarding interventional approaches for VTE treatment (vena cava filters, catheter-guided thrombolysis, thrombosuction) and we discuss current evidences on their efficacy and safety. Moreover, the appropriate indications for their use in daily clinical practice are reviewed.

Emergency reversal of anticoagulation with a three-factor prothrombin complex concentrate in patients with intracranial haemorrhage.

BACKGROUND: Intracranial haemorrhage is a serious and potentially fatal complication of oral anticoagulant therapy. Prothrombin complex concentrates can substantially shorten the time needed to reverse the effects of oral anticoagulants. The aim of this study was to determine the efficacy and safety of a prothrombin complex concentrate for rapid reversal of oral anticoagulant therapy in patients with intracranial haemorrhage. METHODS: Patients receiving oral anticoagulant therapy and suffering from acute intracranial haemorrhage were eligible for this prospective cohort study if their International Normalised Ratio (INR) was higher than or equal to 2.0. The prothrombin complex concentrate was infused at doses of 35-50 IU/kg, stratified according to the initial INR. RESULTS: Forty-six patients (25 males; mean age: 75 years; range 38-92 years) were enrolled. The median INR at presentation was 3.5 (range, 2-9). At 30 minutes after administration of the prothrombin complex concentrate, the median INR was 1.3 (range, 0.9-3), and the INR then declined to less than or equal to 1.5 in 75% of patients. The benefit of the prothrombin complex concentrate was maintained for a long time, since the median INR remained lower than or equal to 1.5 (median, 1.16; range, 0.9-2.2) at 96% of all post-infusion time-points up to 96 hours. No thrombotic complications or significant adverse events were observed during hospitalisation; six patients (13%) died, but none of these deaths was judged to be related to administration of the prothrombin complex concentrate. CONCLUSIONS: Prothrombin complex concentrates are an effective, rapid and safe treatment for the urgent reversal of oral anticoagulation in patients with intracranial haemorrhage. Broader use of prothrombin complex concentrates in this clinical setting appears to be appropriate.