Venous thromboembolism secondary to hospitalization for COVID-19: patient management and long-term outcomes.

Background: Venous thromboembolism (VTE) is a complication of COVID-19 in hospitalized patients. Little information is available on long-term outcomes of VTE in this population. Objectives: We aimed to compare the characteristics, management strategies, and long-term clinical outcomes between patients with COVID-19-associated VTE and patients with VTE provoked by hospitalization for other acute medical illnesses. Methods: This is an observational cohort study, with a prospective cohort of 278 patients with COVID-19-associated VTE enrolled between 2020 and 2021 and a comparison cohort of 300 patients without COVID-19 enrolled in the ongoing START2-Register between 2018 and 2020. Exclusion criteria included age <18 years, other indications to anticoagulant treatment, active cancer, recent (<3 months) major surgery, trauma, pregnancy, and participation in interventional studies. All patients were followed up for a minimum of 12 months after treatment discontinuation. Primary end point was the occurrence of venous and arterial thrombotic events. Results: Patients with VTE secondary to COVID-19 had more frequent pulmonary embolism without deep vein thrombosis than controls (83.1% vs 46.2%, P <.001), lower prevalence of chronic inflammatory disease (1.4% and 16.3%, P <.001), and history of VTE (5.0% and 19.0%, P <.001). The median duration of anticoagulant treatment (194 and 225 days, P = 0.9) and the proportion of patients who discontinued anticoagulation (78.0% and 75.0%, P = 0.4) were similar between the 2 groups. Thrombotic event rates after discontinuation were 1.5 and 2.6 per 100 patient-years, respectively (P = 0.4). Conclusion: The risk of recurrent thrombotic events in patients with COVID-19-associated VTE is low and similar to the risk observed in patients with VTE secondary to hospitalization for other medical diseases.

The prognostic value of respiratory symptoms and performance status in ambulatory cancer patients and unsuspected pulmonary embolism; analysis of an international, prospective, observational cohort study.

BACKGROUND: Optimal risk stratification of unsuspected pulmonary embolism (UPE) in ambulatory cancer patients (ACPs) remains unclear. Existing clinical predictive rules (CPRs) are derived from retrospective databases and have limitations. The UPE registry is a prospective international registry with pre-specified characteristics of ACPs with a recent UPE. The aim of this study was to assess the utility of risk factors captured in the UPE registry in predicting proximate (30-, 90- and 180-day) mortality and how they performed when applied to an existing CPR. OBJECTIVES: To evaluate risk factors for proximate mortality, overall survival, recurrent venous thromboembolism and major bleeding, in the patients enrolled in the UPE registry cohort. METHODS: Data from the 695 ACPs in this registry were subjected to multivariate logistic regression analyses to identify predictors independently associated with proximate mortality and overall survival. The most consistent predictors were applied to the Hull CPR, an existing 5-point prediction rule. RESULTS: The most consistent predictors of mortality were patient-reported respiratory symptoms within 14 days before, and ECOG performance status at the time of UPE. These predictors applied to the Hull-CPR produced a consistent correlation with proximate mortality and overall survival (area under the curve [AUC] = 0.70 [95% CI 0.63, 077], AUC = 0.65 [95% CI 0.60, 070], AUC = 0.64 [95% CI 0.59, 068], and AUC = 0.61, 95% CI 0.57, 0.65, respectively). CONCLUSION: In ACPs with UPE, ECOG performance status logged contemporaneously to the UPE diagnosis and respiratory symptoms prior to UPE diagnosis can stratify mortality risk. When applied to the HULL-CPR these risk predictors confirmed the risk stratification clusters of low-intermediate and high-risk for proximate mortality as seen in the original derivation cohort.

Treatment Decision-Making of Secondary Prevention After Venous Thromboembolism: Data From the Real-Life START2-POST-VTE Register.

Patients with venous thromboembolism (VTE) should receive a decision on the duration of anticoagulant treatment (AT) that is often not easy to make. Sixteen Italian clinical centers included patients with recent VTE in the START2-POST-VTE register and reported the decisions taken on duration of AT in each patient and the reasons for them. At the moment of this report, 472 (66.9%) of the 705 patients included in the registry were told to stop AT in 59.3% and to extend it in 40.7% of patients. Anticoagulant treatment lasted ≥3 months in >90% of patients and was extended in patients with proximal deep vein thrombosis because considered at high risk of recurrence or had thrombophilic abnormalities. d-dimer testing, assessment of residual thrombus, and patient preference were also indicated among the criteria influencing the decision. In conclusion, Italian doctors stuck to the minimum 3 months AT after VTE, while the secondary or unprovoked nature of the event was not seen as the prevalent factor influencing AT duration which instead was the result of a complex and multifactorial evaluation of each patient.

Treatment and Long-Term Clinical Outcomes of Incidental Pulmonary Embolism in Patients With Cancer: An International Prospective Cohort Study.

PURPOSE: Pulmonary embolism is incidentally diagnosed in up to 5% of patients with cancer on routine imaging scans. The clinical relevance and optimal therapy for incidental pulmonary embolism, particularly distal clots, is unclear. The aim of the current study was to assess current treatment strategies and the long-term clinical outcomes of incidentally detected pulmonary embolism in patients with cancer. PATIENTS AND METHODS: We conducted an international, prospective, observational cohort study between October 22, 2012, and December 31, 2017. Unselected adults with active cancer and a recent diagnosis of incidental pulmonary embolism were eligible. Outcomes were recurrent venous thromboembolism, major bleeding, and all-cause mortality during 12 months of follow-up. Outcome events were centrally adjudicated. RESULTS: A total of 695 patients were included. Mean age was 66 years and 58% of patients were male. Most frequent cancer types were colorectal (21%) and lung cancer (15%). Anticoagulant therapy was initiated in 675 patients (97%), of whom 600 (89%) were treated with low-molecular-weight heparin. Recurrent venous thromboembolism occurred in 41 patients (12-month cumulative incidence, 6.0%; 95% CI, 4.4% to 8.1%), major bleeding in 39 patients (12-month cumulative incidence, 5.7%; 95% CI, 4.1% to 7.7%), and 283 patients died (12-month cumulative incidence, 43%; 95% CI, 39% to 46%). The 12-month incidence of recurrent venous thromboembolism was 6.4% in those with subsegmental pulmonary embolism compared with 6.0% in those with more proximal pulmonary embolism (subdistribution hazard ratio, 1.1; 95% CI, 0.37 to 2.9; P = .93). CONCLUSION: In patients with cancer with incidental pulmonary embolism, risk of recurrent venous thromboembolism is significant despite anticoagulant treatment. Patients with subsegmental pulmonary embolism seemed to have a risk of recurrent venous thromboembolism comparable to that of patients with more proximal clots.

Recurrent Thrombotic Events after Discontinuation of Vitamin K Antagonist Treatment for Splanchnic Vein Thrombosis: A Multicenter Retrospective Cohort Study.

It is generally recommended that patients with splanchnic vein thrombosis (SVT) should receive a minimum of 3 months of anticoagulant treatment. However, little information is available on the long-term risk of recurrent thrombotic events. The aim of this study was to evaluate the risk of venous and arterial thrombosis after discontinuation of vitamin K antagonist (VKA) in SVT patients. Retrospective information from a cohort of SVT patients treated with VKA and followed by 37 Italian Anticoagulation Clinics, up to June 2013, was collected. Only patients who discontinued VKA and did not receive any other anticoagulant drug were enrolled in this study. Thrombotic events during follow-up were centrally adjudicated. Ninety patients were included: 33 unprovoked SVT, 27 SVT secondary to transient risk factors, and 30 with permanent risk factors. During a median follow-up of 1.6 years, 6 venous and 1 arterial thrombosis were documented, for an incidence of 3.3/100 patient-years (pt-y). The recurrence rate was highest in the first year after VKA discontinuation (8.2/100'pt-y) and in patients with permanent risk factors (10.2/100'pt-y). Liver cirrhosis significantly increased the risk of recurrence. In conclusion, the rate of recurrent vascular complications after SVT is not negligible, at least in some patient subgroups.

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.

Safety and feasibility of a diagnostic algorithm combining clinical probability, d-dimer testing, and ultrasonography for suspected upper extremity deep venous thrombosis: a prospective management study.

BACKGROUND: Although well-established for suspected lower limb deep venous thrombosis, an algorithm combining a clinical decision score, d-dimer testing, and ultrasonography has not been evaluated for suspected upper extremity deep venous thrombosis (UEDVT). OBJECTIVE: To assess the safety and feasibility of a new diagnostic algorithm in patients with clinically suspected UEDVT. DESIGN: Diagnostic management study. (ClinicalTrials.gov: NCT01324037) SETTING: 16 hospitals in Europe and the United States. PATIENTS: 406 inpatients and outpatients with suspected UEDVT. MEASUREMENTS: The algorithm consisted of the sequential application of a clinical decision score, d-dimer testing, and ultrasonography. Patients were first categorized as likely or unlikely to have UEDVT; in those with an unlikely score and normal d-dimer levels, UEDVT was excluded. All other patients had (repeated) compression ultrasonography. The primary outcome was the 3-month incidence of symptomatic UEDVT and pulmonary embolism in patients with a normal diagnostic work-up. RESULTS: The algorithm was feasible and completed in 390 of the 406 patients (96%). In 87 patients (21%), an unlikely score combined with normal d-dimer levels excluded UEDVT. Superficial venous thrombosis and UEDVT were diagnosed in 54 (13%) and 103 (25%) patients, respectively. All 249 patients with a normal diagnostic work-up, including those with protocol violations (n = 16), were followed for 3 months. One patient developed UEDVT during follow-up, for an overall failure rate of 0.4% (95% CI, 0.0% to 2.2%). LIMITATIONS: This study was not powered to show the safety of the substrategies. d-Dimer testing was done locally. CONCLUSION: The combination of a clinical decision score, d-dimer testing, and ultrasonography can safely and effectively exclude UEDVT. If confirmed by other studies, this algorithm has potential as a standard approach to suspected UEDVT. PRIMARY FUNDING SOURCE: None.

Long-term outcomes of patients with cerebral vein thrombosis: a multicenter study.

BACKGROUND: Little information is available on the long-term clinical outcome of cerebral vein thrombosis (CVT). OBJECTIVES AND METHODS: In an international, retrospective cohort study, we assessed the long-term rates of mortality, residual disability and recurrent venous thromboembolism (VTE) in a cohort of patients with a first CVT episode. RESULTS: Seven hundred and six patients (73.7% females) with CVT were included. Patients were followed for a total of 3171 patient-years. Median follow-up was 40 months (range 6, 297 months). At the end of follow-up, 20 patients had died (2.8%). The outcome was generally good: 89.1% of patients had a complete recovery (modified Rankin Score [mRS] 0-1) and 3.8% had a partial recovery and were independent (mRS 2). Eighty-four per cent of patients were treated with oral anticoagulants and the mean treatment duration was 12 months. CVT recurred in 31 patients (4.4%), and 46 patients (6.5%) had a VTE in a different site, for an overall incidence of recurrence of 23.6 events per 1000 patient-years (95% confidence Interval [CI] 17.8, 28.7) and of 35.1 events/1000 patient-years (95% CI, 27.7, 44.4) after anticoagulant therapy withdrawal. A previous VTE was the only significant predictor of recurrence at multivariate analysis (hazard ratio [HR] 2.70; 95% CI 1.25, 5.83). CONCLUSIONS: The long-term risk of mortality and recurrent VTE appears to be low in patients who survived the acute phase of CVT. A previous VTE history independently predicts recurrent events.

Transplant-finalized salvage of adult acute lymphoblastic leukemia: results of a mitoxantrone- and methotrexate-based regimen in 36 patients.

Idarubicin-based induction programs in acute lymphoblastic leukemia (ALL) account for 75?-?85% of complete remission rate. A small amount of patients exhibit primary refractoriness, and approximately 60% of those achieving a remission eventually relapse. The present study aimed to review the outcome of patients relapsing after or resistant to an idarubicin-based, induction-consolidation regimen (with/without additional high dose cytarabine). The 'ABC' phase II trial consisted of mitoxantrone (50 mg/m(2) over 5 days) associated with high-dose methotrexate (1.5 g/m(2) over 24 h, followed by folinic acid rescue), high-dose methyl-prednisolone (125 mg b.i.d.) and vincristine, plus granulocyte colony-stimulating factor. Eligible patients were treated with two courses ('A' and 'B', the latter with reduced drug dosages), followed by allogeneic or autologous haematopoietic stem cell transplantation (HSCT, 'C'). Thirty-six patients (3 primary resistant, 33 at first marrow relapse) were evaluated. With 'A', 21 achieved a complete remission (CR), 10 were refractory and 5 died early. Eighteen patients received 'B' (with one more CR, for an overall CR rate of 61%) and, eventually, 12 patients had 'C' procedures (7 autologous, 5 allogeneic HSCT). WHO grade >or=3 treatment-related toxicity developed in 50% and 34% of 'A' and 'B' courses, respectively. The median duration of CR was 5.2 (range 0.5-19.7) months and median overall survival was 7.6 (range 0.5-20) months. In spite of 12 HSCTs, there was no long-term survivor. 'ABC' salvage proved feasible and comparable to reported rescue chemotherapic regimens, but the achievement of cure in refractory/relapsing ALL remains an outstanding clinical task.

Prolonged administration of all-trans retinoic acid in combination with intensive chemotherapy and G-CSF for adult acute myelogenous leukemia: single-centre pilot study in different risk groups.

INTRODUCTION: An exploratory trial was conducted to evaluate toxicity and potential therapeutic role of all trans-retinoic acid (ATRA) given long-term together with chemotherapy and G-CSF to adult patients with acute myelogenous leukemia (AML). MATERIALS AND METHODS: ATRA was administered orally at 45 mg/m(2)/day on days 1-14 and 25 mg/m(2)/day on days 15-28 of two standard cycles (idarubicin, etoposide, cytarabine, G-CSF) and of up to three high-dose courses (cytarabine, G-CSF). The results obtained in 19 patients enrolled in the ATRA trial were compared with those from 29 comparable cases treated with the same schedule without ATRA, according to patient risk class and an in vitro study. RESULTS: ATRA was administered for a median of 52 days to the patients selected for study who achieved a remission. ATRA-related toxicity was mostly non-severe apart from high incidence of headache in conjunction with high-dose cytarabine. Complete remission (CR) rate after cycle 1 (54%), kinetics of hematological recovery, postremission treatment realization, disease-free survival (DFS 37.5% at three years) and overall survival (30% at three years) were not different between ATRA-treated and untreated patients. The only significant prognostic factor was the patient risk class, as defined by cytogenetics and other clinical criteria: DFS rate was 57% at three years in standard-risk cases compared to only 19% in the high-risk group, with no influx by ATRA in either category. The in vitro study, in patients with a definite clinical response, failed to document any inhibitory or pro-apoptotic effect of ATRA on AML blast cells. CONCLUSION: As a consequence to these results, the pilot ATRA phase was closed. This study does not suggest a significant role for the present ATRA schedule as an adjunct to standard antileukemic therapy in adult AML.

Phase I trial with escalating doses of idarubicin and multidrug resistance reversal by short-course cyclosporin A, sequential high-dose cytosine arabinoside, and granulocyte colony-stimulating factor for adult patients with refractory acute leukemia.

BACKGROUND AND OBJECTIVES: Patients with refractory acute myeloid or lymphoid leukemia (AML, ALL) were treated with a high-dose regimen comprising idarubicin (IDR) plus short-course cyclosporin A (CsA) as multidrug resistance type-1 (MDR1) blocking agent. The principal aim was to define the maximum tolerated dose (MTD) of IDR, which is reported to be a less MDR1-sensitive anthracycline. The short CsA infusion was patterned after the results of a previous in vitro study. DESIGN AND METHODS: This was a phase I trial, in which eligible patients received high-dose cytarabine (HDAC) 3 g/m(2)/bd on days 1, 2 and 8, 9, and IDR 12.5-20 mg/m(2)/d on days 3 and 10, with increments of 2.5 mg/m(2)/d from the baseline per treatment group. Intravenous CsA infusion started 4 hours before IDR and lasted 12 hours. Recombinant granulocyte colony-stimulating factor (G-CSF) was added from day 11. IDR MTD was evaluated through analysis of regimen-related toxicity (RRT). RESULTS: Eighteen patients were treated (16 AML, 2 ALL; MDR1+: 8/8 studied). Overall response rate was 61%. Toxicity was severe but manageable up to an IDR dose of 17.5 mg/m(2)/d, while grade 4 RRT developed with IDR 20 mg/m(2)/d. High-grade toxicity, not strictly regimen-related, was sometimes observed at lower IDR concentrations in patients with unresolved complications from prior extensive treatments. In keeping, the complete response (CR) rate was 92% (11/12) for patients with an ECOG performance score <2 compared to 0% (0/6) in the others (p=0.000). Apart from that, induction of markedly hypocellular, leukemia-free bone marrow on day 11 was associated with achievement of CR (13 evaluable: CR 8/10 vs 0/3, p=0.035). INTERPRETATION AND CONCLUSIONS: IDR at 17.5 mg/m(2)/d (x2) can be associated with short-course CsA and HDAC for the management of refractory acute leukemias. While this regimen could deserve testing in a larger phase II trial, to document activity in MDR1+ disease, it remains important to select the most suitable patients in order to avoid the occurrence of life-threatening cumulative toxicity.