Risk Factors of Venous Thromboembolism in Noncritically Ill Patients Hospitalized for Acute COVID-19 Pneumonia Receiving Prophylactic-Dose Anticoagulation.

Background: Therapeutic/intermediate-dose heparin reduces the risk of thromboembolic events but increases the risk of major bleeding in patients hospitalized for acute COVID-19 pneumonia. Objectives: To prospectively assess the incidence of objectively proven venous thromboembolism (VTE) and identify predisposing risk factors in a cohort of hospitalized patients with acute COVID-19 pneumonia undergoing prophylactic-dose heparin. Patients and methods: All consecutive patients admitted for acute COVID-19 pneumonia to the General Internal Medicine Unit of Padova University Hospital, Italy between November 2020 and April 2021, and undergoing prophylactic-dose heparin, were enrolled. Demographic and clinical characteristics and laboratory and radiological findings were recorded on admission. Cases were patients who developed VTE during their hospital stay. Univariable and multivariable logistic regression analyses were used to ascertain the risk factors associated with developing in-hospital VTE. Results: 208 patients (median age: 77 years; M/F 98/110) were included; 37 (18%) developed in-hospital VTE during a median follow-up of 10 days (IQR, 4−18). VTE patients were significantly younger (p = 0.004), more obese (p = 0.002), and had a lower Padua prediction score (p < 0.03) and reduced PaO2/FIO2 ratio (p < 0.03) vs. controls. Radiological findings of bilateral pulmonary infiltrates were significantly more frequent in VTE patients than controls (p = 0.003). Multivariable regression showed that obesity (1.75, 95% CI 1.02−3.36; p = 0.04) and bilateral pulmonary infiltrates on X-rays (2.39, 95% CI 1.22−5.69; p = 0.04) were correlated with increased risk of in-hospital VTE. Conclusions: Obesity and bilateral pulmonary infiltrates on imaging may help clinicians to identify patients admitted to medical wards for acute COVID-19 pneumonia at risk of developing VTE despite prophylactic-dose heparin. Further studies are needed to evaluate whether the administration of therapeutic/intermediate-dose heparin may help prevent VTE episodes without further increasing the bleeding risk.

Risk Factors for Post-Thrombotic Syndrome in Patients With a First Proximal Deep Venous Thrombosis Treated With Direct Oral Anticoagulants.

The incidence of post-thrombotic syndrome (PTS) in patients with deep vein thrombosis (DVT) treated with direct oral anticoagulants (DOACs) remains a matter of debate. Hence, our endeavor to investigate a large cohort of patients with a first episode of proximal DVT treated with DOACs to ascertain the incidence and predisposing risk factors for PTS. All consecutive patients referred to the Thrombotic and Haemorrhagic Diseases Unit of Padova University Hospital (Italy) between January 2014 and January 2018 for a first episode of proximal DVT were considered for enrollment. Participants received DOACs for a minimum period of 3 months. PTS was assessed using the Villalta score up to 36 months after DVT diagnosis. Among 769 enrolled patients (M/F 353/416, age range 26-87 years), 152 (19.8%) developed PTS and 30 (3.9%) developed severe PTS. The adjusted hazard ratio was significant for obesity (1.64, 95% CI 1.28-2.39) and DVT site (femoral and/or iliac veins vs popliteal vein) (1.23, 95% CI 1.15-3.00). The incidence of PTS is not negligible in patients with proximal DVT despite the use of DOACs. We identified obesity and iliofemoral DVT as possible risk factors for PTS. Larger prospective studies are needed to confirm our findings and optimize therapeutic strategies.

Potential Association between Distal Deep Vein Thrombosis and Asymptomatic Atherosclerosis.

Background Several studies have previously reported an association between idiopathic proximal deep vein thrombosis (DVT) and atherosclerosis, but whether spontaneous distal DVT is associated with asymptomatic atherosclerosis is still unknown. Methods Ultrasonography of the carotid arteries was done for plaque detection and intima-media thickness (IMT) evaluation, and the ankle-brachial index (ABI) in 116 patients with spontaneous DVT and without symptomatic atherosclerosis. Fifty-seven patients (M/F 19/38, age range 54-78 years) had distal DVT and 59 (M/F 24/35, age range 51-73 years) had proximal DVT. A group of 57 (M/F 21/36, age range 64-70 years) matched subjects acted as controls. Results No significant difference was found in carotid plaques between patients with distal or proximal DVT versus controls ( p > 0.05 in all comparisons). Carotid IMT (mean ± SD) was significantly increased in patients with distal (1.00 ± 0.20 mm) and proximal (0.98 ± 0.16 mm) DVT versus controls (0.88 ± 0.15 mm, p <0.01 in both comparisons). An ABI £ 0.9 was found in 3/57 (5.3%) and 5/59 (8.5%) patients with distal and proximal DVT, respectively versus no controls with abnormal ABI. Conclusion Our results revealed that there may be an association between spontaneous distal DVT and asymptomatic atherosclerosis, and confirmed the known association between idiopathic proximal DVT and asymptomatic atherosclerosis. Larger studies are needed to confirm our results and to evaluate their clinical implications.

Direct Oral Anticoagulants in Patients With Inherited Thrombophilia and Venous Thromboembolism: A Prospective Cohort Study.

Background In this prospective cohort study, we aimed to evaluate the efficacy and safety of direct oral anticoagulants (DOACs) versus heparin/vitamin K antagonists for the treatment of venous thromboembolism (VTE) in patients with inherited thrombophilia. Methods and Results We enrolled consecutive patients with acute VTE and inherited thrombophilia treated with DOACs (cases) or heparin/vitamin K antagonists (controls), matched for age, sex, ethnicity, and thrombophilia type. End points were VTE recurrence and bleeding complications; residual vein thrombosis and post-thrombotic syndrome; VTE recurrence after anticoagulant discontinuation. Two hundred fifty-five cases (age 52.4±17.3 years, Female 44.3%, severe thrombophilia 33.1%) and 322 controls (age 49.7±18.1 years, Female 50.3%, severe thrombophilia 35.1%) were included. The cumulative incidence of VTE recurrence during anticoagulation was 1.09% in cases versus 1.83%, adjusted hazard ratio (HR) 0.67 (95% CI, 0.16-2.77). The cumulative incidence of bleeding was 10.2% in cases versus 4.97%, HR 2.24 (95% CI 1.10-4.58). No major bleedings occurred in cases (versus 3 in controls). No significant differences regarding residual vein thrombosis and post-thrombotic syndrome. After anticoagulant discontinuation, DOACs yielded a significantly lower 2-year VTE recurrence risk versus traditional anticoagulants (HR, 0.61 [95% CI, 0.47-0.82]). Conclusions DOACs and heparin/vitamin K antagonists showed a similar efficacy in treating VTE in patients with thrombophilia. Although major bleeding episodes were recorded solely with heparin/vitamin K antagonists, we noted an overall increased bleeding rate with DOACs. The use of DOACs was associated with a lower 2-year risk of VTE recurrence after anticoagulant discontinuation.

On-treatment platelet reactivity in peripheral and coronary blood in patients undergoing primary PCI for ST-segment elevation myocardial infarction (STEMI).

Dual antiplatelet therapy is recommended in patients undergoing primary percutaneous coronary intervention (p-PCI) for ST-segment elevation myocardial infarction (STEMI). Pre-analytical variables may influence platelet function analysis results. Our aim was to evaluate the on-treatment platelet reactivity in peripheral artery vs coronary blood in patients with STEMI. We enrolled one hundred and nine patients who consecutively underwent p-PCI at Cardiology Unit of Padua University Hospital between June 2014 and June 2015. Before the procedure, all patients received intravenous aspirin 250 mg and either of the thienopyridines; clopidogrel 600 mg, prasugrel 60 mg or ticagrelor 180 mg. ASPI-test and ADP-test using multiple electrode aggregometry (MEA) were performed in samples collected from both a peripheral artery and the culprit coronary artery. 'Low responders' were patients with an ASPI-test or ADP-test value greater than or equal to a pre-established normal range. No significant differences were observed in ASPI-test values between peripheral (19 (median) [3-49 (10-90 percentiles)] U) vs coronary (12 [1-40] U, p = .06) blood and in ADP-test (40 [14-82] U vs 33 [7-79] U, p =.68) blood. In peripheral blood, fifteen (14%) patients were 'low aspirin' and forty-one (38%) 'low thienopyridines' responders. The prevalence of 'low clopidogrel' responders was higher (45%) than prasugrel (36%) and ticagrelor (33%). Similar results were observed in coronary blood. In patients undergoing p-PCI for STEMI, MEA platelet function observed in coronary arteries was consistent with peripheral artery blood's independently of the antiplatelet drug used. The clinical significance of peripheral and coronary on-aspirin/thienopyridines platelet reactivity needs further clarification.

Circulating microparticles and the risk of thrombosis in inherited deficiencies of antithrombin, protein C and protein S.

Many subjects carrying inherited thrombophilic defects will never experience venous thromboembolism (VTE) while other individuals developed recurrent VTE with no known additional risk factors. High levels of circulating microparticles (MP) have been associated with increased risk of VTE in patients with factor V Leiden and prothrombin G20210A mutation, suggesting a possible contribution of MP in the hypercoagulability of mild genetic thrombophilia. The role of MP as additional risk factor of VTE in carriers of natural clotting inhibitors defects (severe thrombophilia) has never been assessed. Plasma levels of annexin V-MP, endothelial-derived MP (EMP), platelet-derived MP (PMP), tissue factor-bearing MP (TF+) and the MP procoagulant activity (PPL) were measured in 132 carriers of natural anticoagulant deficiencies (25 antithrombin, 63 protein C and 64 protein S defect) and in 132 age and gender-matched healthy controls. Carriers of natural anticoagulant deficiencies, overall and separately considered, presented with higher median levels of annexin V-MP, EMP, PMP, TF+MP and PPL activity than healthy controls (p< 0.001, < 0.001, < 0.01, 0.025 and 0.03, respectively). Symptomatic carriers with a previous episode of VTE had significantly higher median levels of annexin-V MP than those without VTE (p=0.027). Carriers with high levels of annexin V-MP, EMP and PMP had an adjusted OR for VTE of 3.36 (95% CI, 1.59 to 7.11), 9.26 (95% CI, 3.55 to 24.1) and 2.72 (95%CI, 1.16 to 6.38), respectively. Elevated levels of circulating MP can play a role in carriers of mild and severe inherited thrombophilia. The clinical implications of this association remain to be defined.

Comparison of four scores to predict major bleeding in patients receiving anticoagulation for venous thromboembolism: findings from the RIETE registry.

Stratification of the individual bleeding risk prior to initiation of anticoagulation in patients with acute venous thromboembolism (VTE) has the potential to assist clinicians in making decisions about the proper intensity and duration of antithrombotic therapy. It is unclear which of the validated and internationally accepted scores recommended for the achievement of this important task has the best predictive value. We compared the predictive value of four validated scores (by Landefeld, Beyth, Kuijer and Ruiz-Gimenez, respectively) for the development of major bleeding complications occurring in the first 3 months in patients with acute VTE treated with conventional anticoagulation. Based on the population of RIETE Registry (international registry of patients with acute VTE), we identified those patients presenting all the required prognostic variables, and then calculated the ability of each score for predicting the bleeding risk. Of 40,265 eligible patients, we identified 8,717 meeting the recruitment criteria. Overall, 0.9 % of patients experienced at least one episode of major bleeding within 90 days of the index event. The proportion of patients classified as having a low risk varied between 1.2 and 3.7 %, that of patients having an intermediate risk between 76 and 93 %, and that of patients classified as having a high risk between 6.1 and 18 %. The area under the receiver operating characteristic ranged between 0.55 and 0.60, the positive predictive value between 1.5 and 3.2, and the likelihood ratio between 0.72 and 1.59. In conclusion, all four scores show a very low ability to predict the bleeding risk in patients with acute VTE undergoing conventional anticoagulation.

What are the pharmacotherapy options for treating venous thromboembolism in cancer patients?

INTRODUCTION: Venous thromboembolism (VTE) is a frequent complication in patients with malignancies. The treatment of VTE disorders in cancer patients remains a difficult clinical task. AREAS COVERED: Current evidence on the most appropriate initial and long-term treatment of cancer patients with VTE was addressed, as was the management of recurrent VTE despite anticoagulation, the management of incidentally detected isolated pulmonary embolism (PE), the potential role of the novel direct oral anticoagulants and the impact of low-molecular-weight heparin (LMWH) on cancer evolution. EXPERT OPINION: LMWHs are the cornerstone of VTE treatment in cancer patients. The intensity and duration of treatment are dependent on several factors that need to be individually evaluated. The novel oral anticoagulants should be investigated more carefully before being routinely implemented in the treatment of cancer-associated VTE. Incidentally detected isolated sub-segmental PE is unlikely to require systematic full-dose anticoagulation. Evidence favoring an impact of LMWH on survival in cancer patients is weak.

Thigh-length versus below-knee compression elastic stockings for prevention of the postthrombotic syndrome in patients with proximal-venous thrombosis: a randomized trial.

Although below-knee compression elastic stockings (CES) are effective for the prevention of the postthrombotic syndrome (PTS), a substantial number of patients with deep venous thrombosis still develop PTS. In the present open-label, randomized clinical trial, we compared thigh-length with below-knee CES for the prevention of PTS. A total of 267 patients with the first episode of proximal deep venous thrombosis were randomized to wear either thigh-length or below-knee CES for 2 years. After 3, 6, 12, 18, 24, and 36 months, they were assessed for PTS manifestations according to the Villalta scale. PTS developed in 44 (32.6%) of the 135 patients randomized to thigh-length CES and in 47 (35.6%) of the 132 allocated to below-knee CES, for an adjusted hazard ratio of 0.93 (95% confidence interval, 0.62-1.41). Severe PTS developed in 3 patients in each group. CES-related side effects developed in 55 (40.7%) of the 135 patients allocated to thigh-length CES and in 36 (27.3%) of those randomized to the below-knee group (P = .017), and led to premature discontinuation of their use in 29 (21.5%) and 18 (13.6%) patients, respectively. We conclude that thigh-length CES do not offer a better protection against PTS than below-knee CES and are less well tolerated.

Optimal duration of anticoagulation in patients with venous thromboembolism.

The risk of recurrent venous thromboembolism (VTE) approaches 40 per cent of all patients after 10 yr of follow up. This risk is higher in patients with permanent risk factors of thrombosis such as active cancer, prolonged immobilization from medical diseases, and antiphospholipid syndrome; in carriers of several thrombophilic abnormalities, including deficiencies of natural anticoagulants; and in patients with unprovoked presentation. Patients with permanent risk factors of thrombosis should receive indefinite anticoagulation, consisting of subtherapeutic doses of low molecular weight heparin in cancer patients, and oral anticoagulants in all other conditions. Patients whose VTE is triggered by major surgery or trauma should be offered three months of anticoagulation. Patients with unprovoked VTE, including carriers of thrombophilia, and those whose thrombotic event is associated with minor risk factors (such as hormonal treatment, minor injuries, long travel) should receive at least three months of anticoagulation. The decision as to go on or discontinue anticoagulation after this period should be individually tailored and balanced against the haemorrhagic risk. Post-baseline variables, such as the D-dimer determination and the ultrasound assessment of residual thrombosis can help identify those patients in whom anticoagulation can be safely discontinued. As a few emerging anti-Xa and anti-IIa compounds seem to induce fewer haemorrhagic complications than conventional anticoagulation, while preserving at least the same effectiveness, these have the potential to open new scenarios for decisions regarding the duration of anticoagulation in patients with VTE.

Prevalence of heart diseases in patients with pulmonary embolism with and without peripheral venous thrombosis: findings from a cross-sectional survey.

BACKGROUND: In up to 80% of patients with pulmonary embolism (PE) no peripheral symptomatic thrombosis can be identified. Whether the heart may represent a source of PE is unknown. METHODS: We conducted a cross-sectional survey of patients who were 60 years or older and were discharged from the hospitals of Veneto region, Italy between 2000 and 2006 with the diagnosis of PE. We compared the prevalence of several acute and chronic heart diseases in patients discharged with the diagnosis of PE alone with that of patients with co-occurring symptomatic peripheral deep venous thrombosis (PE/DVT). RESULTS: Out of 11,236 eligible patients, 9079 (81%) were discharged with the diagnosis of PE alone, and 2157 with that of PE/DVT. 3239 of the 9079 (35.7%) patients with isolated PE, and 666 of the 2157 (30.9%) with PE/DVT had at least one heart disease. The adjusted odds ratio (OR) for having at least one heart disease in patients with isolated PE as compared to those with PE/DVT was 1.26 (95% CI, 1.13-1.40). The heart diseases that significantly contributed to the study results were all-cause cardiomyopathies (adjusted OR, 2.31; 95% CI, 1.37-3.89), all-cause heart failure (1.82; 1.45-2.27), coronary heart disease (1.28; 1.08-1.52), and atrial fibrillation or flutter (1.28; 1.08-1.51). CONCLUSIONS: There is an association between isolated PE and a number of heart diseases. The results of our survey generate the hypothesis that in older patients several heart diseases may directly account for the development of PE. Prospective studies are needed to confirm this hypothesis.

Potential role of thrombelastography in the monitoring of acquired factor VIII inhibitor hemophilia A: report on a 78-year-old woman with life-threatening bleedings.

A 78-year-old woman was admitted to our hospital because of syncope associated with hematomas in both legs. Acquired hemophilia A (AHA) with a low antifactor VIII antibodies activity was diagnosed. Whole blood (WB) thrombelastographic profile depicted a hypocoagulable state. During hospitalization, the patient experienced life-threatening bleedings in the neck and in the right thigh. FVIII concentrates and rFVIIa was safe and effective in controlling acute hemorrhagic symptoms. Immunosuppressive therapy was used successfully to eradicate the inhibitor. At discharge, FVIII inhibitor was absent and thrombelastogram showed a normal profile. Our report confirms that AHA is a heterogeneous condition in terms of risk of bleeding. Even though the criteria for the diagnosis of AHA is quite well defined, a laboratory test useful to predict the bleeding risk and monitor the response to treatment is lacking. ROTEM profile appears to be correlated with the response to treatment and with the eradication of the inhibitor.

Endothelial dysfunction in patients with spontaneous venous thromboembolism.

BACKGROUND AND OBJECTIVES: A high incidence of atherosclerotic lesions and cardiovascular events has been reported in patients with spontaneous venous thromboembolism. Endothelial dysfunction is an early marker of atherosclerosis and has predictive value for ischemic events. We have evaluated endothelial function in patients with a history of spontaneous venous thromboembolism. DESIGN AND METHODS: Patients with a history of symptomatic, objectively confirmed, spontaneous venous thromboembolism were included in a case-control study. Exclusion criteria were any known risk factors for cardiovascular diseases, other conditions associated with endothelial dysfunction, estro-progestinic therapy or pregnancy. Controls were age- (+/-5 years) and sex-matched subjects with the same exclusion criteria but without previous venous thromboembolism. Endothelial function was evaluated by the non-invasive measurement of flow-mediated vasodilation of the brachial artery and of plasma markers of endothelium activation; platelet activation parameters were also measured. RESULTS: Twenty-eight cases (8 females; mean age 59+/-15 years) and 28 controls (8 females; mean age 58+/-15) were studied. Flow-mediated vasodilation was 3.5+/-0.6% in cases (95% CIs: 2.2 to 4.8) and 5.7+/-0.6% (4.2 to 6.8) in controls (p=0.015). Brachial artery blood flow and hyperemic blood flow did not differ between the two groups. Plasma von Willebrand factor and soluble P-selectin levels were significantly higher in patients with venous thromboembolism, while plasma soluble CD40 ligand and urinary 11-dehydro-TxB2 levels were similar in cases and controls. INTERPRETATION AND CONCLUSIONS: Patients with spontaneous venous thromboembolism have endothelial dysfunction, unlike age- and sex- matched controls. This finding suggests that spontaneous venous thromboembolism may be a condition associated with an enhanced risk of atherosclerosis.

Postthrombotic syndrome.

Despite considerable progress in the diagnosis and treatment of deep vein thrombosis (DVT) of the lower extremities, one of every three patients will develop postthrombotic sequelae within 2 years; these sequelae are severe in approximately 20% of cases and produce considerable socioeconomic consequences. Among factors potentially related to the development of the postthrombotic syndrome (PTS) are older age, obesity, insufficient oral anticoagulant therapy, and recurrent ipsilateral thrombosis. Whether the extent and location of the initial thrombosis are associated with the development of PTS is controversial. Based on recent findings, the lack of vein recanalization within the first 6 months appears to be an important predictor of PTS, whereas the development of transpopliteal venous reflux is not. The diagnosis of PTS can be made on clinical grounds for patients with a history of DVT. The combination of a standardized clinical evaluation with the results of compression ultrasonography and Doppler ultrasound helps diagnose or exclude a previous proximal vein thrombosis. According to the results of recent clinical studies, the prompt administration of adequate compression elastic stockings in patients with symptomatic DVT has the potential to reduce the frequency of late PTS development by half. The management of this condition is demanding and often frustrating. However, when carefully supervised and instructed to wear proper elastic stockings, more than 50% of patients will either remain stable or improve during long-term follow-up. Clinical presentation helps predict the prognosis; the outcome of patients who refer with initially severe manifestations is more favorable than that of patients whose symptoms deteriorate progressively over time.