Gynecological Cancer and Venous Thromboembolism: A Narrative Review to Increase Awareness and Improve Risk Assessment and Prevention.

The prevention and appropriate management of venous thromboembolism in cancer patients is of paramount importance. However, the literature data report an underestimation of this major problem in patients with gynecological cancers, with an inconsistent venous thromboembolism risk assessment and prophylaxis in this patient setting. This narrative review provides a comprehensive overview of the available evidence regarding the management of venous thromboembolism in cancer patients, focusing on the specific context of gynecological tumors, exploring the literature discussing risk factors, risk assessment, and pharmacological prophylaxis. We found that the current understanding and management of venous thromboembolism in gynecological malignancy is largely based on studies on solid cancers in general. Hence, further, larger, and well-designed research in this area is needed.

Inappropriate Underdosing of Direct Oral Anticoagulants in Atrial Fibrillation Patients: Results from the START2-AF Registry.

Background: Direct oral anticoagulants (DOACs) are recommended for stroke prevention in non-valvular atrial fibrillation (NVAF) patients. We aimed to describe the prevalence of inappropriate DOACs dose prescription in the START2-AF Registry, the outcomes according to the appropriateness of the dosage, and the factors associated with inappropriate dose prescription. Methods: Patients' demographics and clinical data were prospectively collected as electronic files in an anonymous form on the website of the START2-Registry; DOACs dosage was determined to be appropriate when prescribed according to the European Heart Rhythm Association Guidelines. Results: We included 5943 NVAF patients on DOACs; 2572 (46.3%) were female patients. The standard dose (SD) was prescribed to 56.9% of patients and the low dose (LD) was prescribed to 43.1% of patients; 38.9% of all NVAF patients received an inappropriate LD DOAC and 0.3% received inappropriate SD. Patients treated with LD DOAC had a significantly higher rate of all bleedings (RR 1.5; 95% CI 1.2-2.0), major bleedings (RR 1.8; 95% CI 1.3-1.7), and mortality (RR 2.8; 95% CI 1.9-4.1) with respect to patients treated with SD DOAC. No difference was found among patients treated with appropriate and inappropriate LD regarding bleeding, thrombotic, and mortality rates. Age, body weight <60 kg, and renal failure were significantly associated with inappropriate LD DOAC prescription. Conclusions: Inappropriate LD DOACs in NVAF patients is not associated with a reduction in bleeding risk, nor with an increased thrombotic risk. Instead, it is associated with higher mortality rate, suggesting that, in clinical practice, underdosing is preferred for patients at particularly high risk for adverse events.

D-dimer and risk of venous thromboembolism recurrence: Comparison of two studies with similar designs but different laboratory and clinical results.

BACKGROUND: D-dimer testing may help deciding the duration of anticoagulation in subjects at high risk of venous thromboembolism (VTE) recurrence. Two management studies on this issue have been published (DULCIS in 2014 and APIDULCIS in 2022). They had similar designs but had important different results. Aim of this article is to compare their results. METHODS: Both studies were finalized to extend anticoagulation [with vitamin K anticoagulants (VKAs) in DULCIS or apixaban 2.5 mg BID (kindly provided by BMS-Pfizer Collaboration) in APIDULCIS] only in patients with positive D-dimer results. RESULTS: More D-dimer assays resulted positive in APIDULCIS than in DULCIS (61.1 % vs 47.7 %, respectively; p < 0.0001). While only 4 (0.5 %) refused low dose apixaban in APIDULCIS, the 22.6 % of patients with positive D-dimer refused to resume VKAs in DULCIS; their rates of recurrence were 187 and 8.8 per 100 person-years, respectively (incidence rate ratio [IRR]: 21.2). The incidence of bleeding was low in those receiving apixaban vs those who resumed VKAs (0.4 vs 2.3 per 100 person-years, respectively; IRR 0.17;). While the recurrence rate was low and similar in the studies in subjects who resumed anticoagulation, it was significantly higher in APIDULCIS than in DULCIS in those who stopped anticoagulation for negative D-dimer (5.6 vs 3.0 per 100 person-years, respectively; IRR 1.9). CONCLUSION: The low dose Apixaban for extended VTE treatment is effective and safe, and well accepted by patients. Why subjects who stopped anticoagulation for negative D-dimer had a higher recurrence rate in APIDULCIS than in DULCIS remains to be explained.

Sex Differences in Clinical Presentation of Lower Extremity Deep Vein Thrombosis.

Background: Differences between men and women in the clinical features and extent of lower limb deep vein thrombosis (DVT) may influence DVT diagnostic algorithms involving pretest clinical probability (PTP) assessment, D-dimer, and compression ultrasonography (CUS). Aims: To assess differences in DVT clinical presentation between men and women and their effect on PTP and D-dimer. Methods: We conducted a retrospective study in outpatients referred for suspected DVT of the lower limbs to our vascular emergency department from January 2005 to December 2019. Patients underwent PTP assessment with the Wells score, D-dimer testing, and CUS. Results: More women were referred for suspected DVT than men (M/F: 1,785/2,821; F: 61.4%; p < 0.0001). Women were older than men (median age: 71 vs. 67 years; p = 0.0001), DVT was diagnosed in 436 patients (9.4%) but in more men than women (M: 210 [11.8%] vs. F: 226 [8%]; p = 0.0002), with more proximal DVT in men than women (M: 131 7.3% vs. F: 124 [4.4%]; p = 0.00021). PTP was more likely in men (355 [19.9%]) than women (455 [16.2%]) (p = 0.0011); more men had swelling in the entire limb, increased calf circumference by >3 cm compared with the contralateral limb, and pitting edema, than women. D-dimer levels (available in 65% of patients) were more frequently positive in women with DVT than in men (94.6% vs. 85.7%; p = 0.016). However, a positive D-dimer and/or likely PTP was similarly frequent in men (92%) and women (96%) with DVT. Conclusions: More women than men are referred for suspected DVT, and men have a higher prevalence of proximal DVT. However, current algorithms for DVT diagnosis perform similarly in men and in women.

D-Dimers in diagnosis and prevention of venous thrombosis: recent advances and their practical implications.

D­Dimers derive from degradation of cross­linked fibrin by plasmin, and thus their level is a marker of coagulation and fibrinolytic system activation. Guidelines recommend that D­dimers are determined if the pretest probability (PTP) is low or intermediate, to exclude venous thromboembolism (VTE), either deep vein thrombosis or pulmonary embolism, and to avoid imaging tests. If the PTP is high or D­dimer level is above the suggested thresholds, imaging is recommended. D­Dimer assays offer high sensitivity and low specificity, as D­dimer levels can be above the threshold in several other conditions than thrombosis, and they increase with age. As a result, there have been several proposals to improve the diagnostic accuracy of D­dimer levels by adjusting the cutoffs according to patient characteristics, such as age, PTP, pregnancy, renal function, or cancer. D­Dimer levels can also predict clinical severity of COVID­19, and escalated anticoagulation based on D­dimer levels can be associated with a lower risk of mortality in patients with severe COVID­19. Finally, D­dimer levels have been incorporated in prediction models for recurrent VTE to help identify patients who may benefit from prolonged anticoagulation.

Incidence and clinical outcomes of heparin-induced thrombocytopenia: 11 year experience in a tertiary care university hospital.

Heparin-induced thrombocytopenia (HIT) is a rare immuno-mediated adverse reaction with high thrombotic and mortality risk. To evaluate incidence and outcomes of HIT cases diagnosed at a tertiary care hospital from 2007 to 2018. A retrospective study was conducted. Patients with suspected HIT underwent 4Ts score assessment and anti-heparin PF4 IgG antibodies ELISA screening test. If the latter was positive, platelet aggregation test (PAT) was performed. If the latter was positive, any form of heparin was stopped, alternative anticoagulants were started and then overlapped with warfarin. HIT incidence was calculated by dividing HIT cases by the mean yearly number of admitted patients over 11 years. Follow-up was 90 days. Among 2125 screening tests, 96 (4.5%) were positive with confirmatory PAT in 82/90 (3.8% for missing data in 6). Median age was 75; 39 patients were surgical and 51 medical. The median 4Ts score was 5. Unfractionated heparin was employed in 34 (37%). HIT incidence was 0.16/1000/patient/years (95% CI: 0.12-0.23) in surgical and 0.15/1000/patient/years (95%: 0.12-0.20) in medical patients. HIT with thrombosis (HIT-T) was observed in 31 patients (0.05/1000/patient/years 95% CI: 0.04-0.1), with venous thromboses in 25 (80%). HIT without thrombosis was observed in 59 patients (0.1/1000 patient/years; 95% CI: 0.08-0.13, twofold vs HIT-T). All cause mortality was 25.5% (95% CI: 17.6-35.4), major bleeding 7.7% (95% CI:3.2-15.3), and thromboembolic complications 3.3% (95% CI:1.1-9.3). HIT is a rare event with high mortality, despite the use of non heparin anticoagulants.

Age-adjusted D-dimer, clinical pre-test probability-adjusted D-dimer, and whole leg ultrasound in ruling out suspected proximal and calf deep venous thrombosis.

D-dimer (DD) and ultrasonography (US) are part of the diagnostic workup for lower-extremity deep vein thrombosis (DVT). Recent studies have shown that adjusting DD level cut-offs by age or clinical pre-test probability (PTP) decreases the use of US. We compared diagnostic accuracy of PTP-adjusted DD and age-adjusted DD in 3883 patients (F: 61.1%; age: 65.3 ± 16.8 y) referred to our unit for clinically suspected DVT. All patients underwent clinical evaluation, DD, and US. Proximal DVT was detected in 477 (12.4%) patients, and distal DVT was isolated in 342 (8.9%) patients. In the remaining 3064 patients there were 23 venous thromboembolic events (0.75%, 95% CI: 0.50-1.12) during the 3-month follow-up. The specificities of DD, age-adjusted DD, and PTP-adjusted DD in patients without high PTP levels were 47% (95% CI: 45-49), 61% (95% CI: 59-62), and 67% (95% CI: 65-68), respectively. The negative predictive value (NPV) was 96% (95% CI: 95-97) for all diagnostic strategies. When only proximal DVTs were considered, the NPV increased to 99% (95% CI: 98-99). US was avoided in 37% (95% CI: 36-38) of patients with a fixed cut-off DD, 48% (95% CI: 47-50) with age-adjusted DD, and 52% (95% CI: 51-54) with PTP-adjusted DD. The failure rate for all DVTs of DD, age-adjusted DD, and PTP-adjusted DD was 2.0% (95% CI: 1.6-2.5), 2.7% (95% CI: 2.2-3.2), and 2.5% (95% CI: 2.1-3.0), respectively. Compared with the standard DD cut-off, both age-adjusted and PTP-adjusted DD reduced the proportion of patients who required US at the cost of a small increase in failure rate.

Venous Thromboembolism in Women of Childbearing Age: Insights from the START Registry.

BACKGROUND: Women of childbearing age are exposed to venous thromboembolic risk mainly for pregnancy and use of oral contraceptives. The impact of risk factors (RF) on venous thromboembolism (VTE) in these circumstances is still unclear. AIM: In the context of START registry, we aimed to investigate the weight of a series of RF on the occurrence of pregnancy- or combined oral contraceptive (COC)-associated VTE. MATERIALS AND METHODS: We selected all women included in the START for VTE occurred between 18-42 years and compared those with a first or recurrent pregnancy/postpartum- (group A) or COC-VTE (group B) with those who had VTE outside these circumstances (group C). Final analysis included a cohort of 532 women. Follow-up data showed that there were no significant differences between the groups in terms of thrombotic and haemorrhagic complications. As for pregnancy-associated VTE, the overall outcome was good in terms of both maternal and fetal prognosis. RESULTS: In a binary model of logistic regression, correcting for potential confounders, VTE family history conferred a significant and independent higher risk of COC-VTE compared with group C. Similarly, comparison between group A and C documented that family history significantly affected the risk of pregnancy-associated VTE. VTE in the group C was significantly associated with older age. Lastly, smoke was a significant risk factor for pregnancy/postpartum VTE when group A and group B were compared. CONCLUSION: Present data suggest that in the setting of fertile women, family history of VTE has a greater role in predicting COC- and pregnancy/postpartum- VTE than outside these circumstances.

Platelet RNA sequencing for cancer screening in patients with unprovoked venous thromboembolism: a prospective cohort study.

BACKGROUND: Platelet RNA sequencing has been shown to accurately detect cancer in previous studies. OBJECTIVES: To compare the diagnostic accuracy of platelet RNA sequencing with standard-of-care limited cancer screening in patients with unprovoked venous thromboembolism (VTE). METHODS: Patients aged ≥40 years with unprovoked VTE were recruited at 13 centers and followed for 12 months for cancer. Participants underwent standard-of-care limited cancer screening, and platelet RNA sequencing analysis was performed centrally at study end for cases and selected controls. Sensitivity and specificity were calculated, using the predefined primary positivity threshold of 0.54 for platelet RNA sequencing aiming at 86% test sensitivity, and an additional predefined threshold of 0.89 aiming at 99% test specificity. RESULTS: A total of 476 participants were enrolled, of whom 25 (5.3%) were diagnosed with cancer during 12-month follow-up. For each cancer patient, 3 cancer-free patients were randomly selected for the analysis. The sensitivity of limited screening was 72% (95% CI, 52-86) at a specificity of 91% (95% CI, 82-95). The area under the receiver operator characteristic for platelet RNA sequencing was 0.54 (95% CI, 0.41-0.66). At the primary positivity threshold, all patients had a positive test, for a sensitivity estimated at 100% (95% CI, 87-99) and a specificity of 8% (95% CI, 3.7-16.4). At the secondary threshold, sensitivity was 68% (95% CI, 48-83; p value compared with limited screening 0.71) at a specificity of 36% (95% CI, 26-47). CONCLUSION: Platelet RNA sequencing had poor diagnostic accuracy for detecting occult cancer in patients with unprovoked VTE with the current algorithm.

Capsular Warning Syndrome: Features, Risk Profile, and Prognosis in a Large Prospective TIA Cohort.

INTRODUCTION: Features and prognosis of capsular warning syndrome (CWS) have been poorly investigated prospectively. AIMS: The study aimed to characterize CWS clinical features, risk profile, short- and long-term prognosis, among a large TIA cohort. METHODS: Prospective cohort study of consecutive TIAs was conducted from August 1, 2010, to December 31, 2017. Demographic and clinical characteristics, risk profile, primary (stroke and composite outcome) and secondary (TIA recurrence, cerebral hemorrhage, new onset atrial fibrillation) outcomes were compared between CWS, lacunar (L), and nonlacunar (NL) TIAs. RESULTS: 1,035 patients (33 CWS, 189 L-TIAs, 813 NL-TIAs) were enrolled. Newly diagnosed (ND) hypertension, hypercholesterolemia, cigarette smoking, and leukoaraiosis were independent risk factors of CWS (p < 0.05). CWS showed the highest stroke (30.3% vs. 0.5% and 1.5% for L-TIAs and NL-TIAs, respectively) and composite outcome risk at follow-up (p < 0.001), but better 3-month post-stroke prognosis (mRS 0-2 90.0% vs. 36.8%; p = 0.002). CWS-related stroke mostly occurred <48 h (80.0%) and had a small vessel occlusion etiology (100%), affecting more often the internal capsule (60.0%). Dual antiplatelet therapy (DAPT) versus single antiplatelet therapy was associated with lower 3-month cumulative stroke incidence (12.5% vs. 57.1%; p = 0.010). Intravenous thrombolysis (IVT) showed similar 3-month efficacy and safety in strokes after TIAs groups (median mRS 0, IQR 0-1; p = 0.323). CONCLUSIONS: CWS is associated with higher stroke risk and better functional prognosis than L- and NL-TIAs. CWS risk profile is consistent with severe small vessel disease, and ND hypertension could represent a major risk factor. DAPT and IVT seem effective and safe in preventing and treating stroke following CWS.

D-dimer and reduced-dose apixaban for extended treatment after unprovoked venous thromboembolism: the Apidulcis study.

D-dimer assay is used to stratify patients with unprovoked venous thromboembolism (VTE) for the risk of recurrence. However, this approach was never evaluated since direct oral anticoagulants are available. With this multicenter, prospective cohort study, we aimed to assess the value of an algorithm incorporating serial D-dimer testing and administration of reduced-dose apixaban (2.5 mg twice daily) only to patients with a positive test. A total of 732 outpatients aged 18 to 74 years, anticoagulated for ≥12 months after a first unprovoked VTE, were included. Patients underwent D-dimer testing with commercial assays and preestablished cutoffs. If the baseline D-dimer during anticoagulation was negative, anticoagulation was stopped and testing repeated after 15, 30, and 60 days. Patients with serially negative results (286 [39.1%]) were left without anticoagulation. At the first positive result, the remaining 446 patients (60.9%) were given apixaban for 18 months. All patients underwent follow-up planned for 18 months. The study was interrupted after a planned interim analysis for the high rate of primary outcomes (7.3%; 95% confidence interval [CI], 4.5-11.2), including symptomatic proximal deep vein thrombosis (DVT) or pulmonary embolism (PE) recurrence, death for VTE, and major bleeding occurring in patients off anticoagulation vs that in those receiving apixaban (1.1%; 95% CI, 0.4-2.6; adjusted hazard ratio [HR], 8.2; 95% CI, 3.2-25.3). In conclusion, in patients anticoagulated for ≥1 year after a first unprovoked VTE, the decision to further extend anticoagulation should not be based on D-dimer testing. The results confirmed the high efficacy and safety of reduced-dose apixaban against recurrences. This trial was registered at www.clinicaltrials.gov as #NCT03678506.

Thromboembolic Disease in Patients With Cancer and COVID-19: Risk Factors, Prevention and Practical Thromboprophylaxis Recommendations-State-of-the-Art.

Cancer and COVID-19 are both well-established risk factors predisposing to thrombosis. Both disease entities are correlated with increased incidence of venous thrombotic events through multifaceted pathogenic mechanisms involving the interaction of cancer cells or SARS-CoV2 on the one hand and the coagulation system and endothelial cells on the other hand. Thromboprophylaxis is recommended for hospitalized patients with active cancer and high-risk outpatients with cancer receiving anticancer treatment. Universal thromboprophylaxis with a high prophylactic dose of low molecular weight heparins (LMWH) or therapeutic dose in select patients, is currentlyindicated for hospitalized patients with COVID-19. Also, prophylactic anticoagulation is recommended for outpatients with COVID-19 at high risk for thrombosis or disease worsening. However, whether there is an additive risk of thrombosis when a patient with cancer is infected with SARS-CoV2 remains unclear In the current review, we summarize and critically discuss the literature regarding the epidemiology of thrombotic events in patients with cancer and concomitant COVID-19, the thrombotic risk assessment, and the recommendations on thromboprophylaxis for this subgroup of patients. Current data do not support an additive thrombotic risk for patients with cancer and COVID-19. Of note, patients with cancer have less access to intensive care unit care, a setting associated with high thrombotic risk. Based on current evidence, patients with cancer and COVID-19 should be assessed with well-established risk assessment models for medically ill patients and receive thromboprophylaxis, preferentially with LMWH, according to existing recommendations. Prospective trials on well-characterized populations do not exist.

Thrombotic burden, D-dimer levels and complete compression ultrasound for diagnosis of acute symptomatic deep vein thrombosis of the lower limbs.

BACKGROUND: Diagnostic algorithms for deep vein thrombosis (DVT) include D-dimer for its high negative predictive value, thus reducing the need for imaging. Small thrombi may be associated with low D-dimer levels, increasing false negatives. AIM: To assess the sensitivity and thus the false negative rates of standard and age-adjusted D-dimer cut offs for isolated distal DVT (IDDVT) in outpatients. MATERIALS AND METHODS: We enrolled consecutive outpatients with suspected DVT of the lower limbs referring to our vascular emergency department from 2009 to 2018. Patients underwent D-dimer testing (STA, Stago, cut-off: 500 µg/L), pretest clinical probability (PTP) evaluation and complete compression ultrasonography. Follow-up was 3 months. RESULTS: Among 3948 patients (M:1554-39%, median age 69), 486 proximal DVTs (12.3%) and 348 IDDVTs (8.8%) were diagnosed. Median D-dimer was higher in proximal than IDDVT (3960 vs 1400 µgr/L; p = 0.001). The false negative rate of the standard D-dimer cut-off was 2% (95%CI: 0.8-3.2%) for proximal DVT and 14.7% (95% CI: 11-81%) for IDDVT. The false negative rate of the age-adjusted cut-off was 4.9% (3-7%) for proximal DVT and 19.5% (95% CI: 15.4-24.7%) for IDDVT. CONCLUSIONS: Small calf thrombi are associated with low D-dimer levels, and age-adjusted D-dimer may be below the cut-off more frequently in subjects with IDDVT than standard cut-off D-dimer, although such D-dimer levels might exclude IDDVT that require treatment.

The Post-thrombotic Syndrome-Prevention and Treatment: VAS-European Independent Foundation in Angiology/Vascular Medicine Position Paper.

Importance: The post-thrombotic syndrome (PTS) is the most common long-term complication of deep vein thrombosis (DVT), occurring in up to 40-50% of cases. There are limited evidence-based approaches for PTS clinical management. Objective: To provide an expert consensus for PTS diagnosis, prevention, and treatment. Evidence-Review: MEDLINE, Cochrane Database review, and GOOGLE SCHOLAR were searched with the terms "post-thrombotic syndrome" and "post-phlebitic syndrome" used in titles and abstracts up to September 2020. Filters Were: English, Controlled Clinical Trial / Systematic Review / Meta-Analysis / Guideline. The relevant literature regarding PTS diagnosis, prevention and treatment was reviewed and summarized by the evidence synthesis team. On the basis of this review, a panel of 15 practicing angiology/vascular medicine specialists assessed the appropriateness of several items regarding PTS management on a Likert-9 point scale, according to the RAND/UCLA method, with a two-round modified Delphi method. Findings: The panelists rated the following as appropriate for diagnosis: 1-the Villalta scale; 2- pre-existing venous insufficiency evaluation; 3-assessment 3-6 months after diagnosis of iliofemoral or femoro-popliteal DVT, and afterwards periodically, according to a personalized schedule depending on the presence or absence of clinically relevant PTS. The items rated as appropriate for symptom relief and prevention were: 1- graduated compression stockings (GCS) or elastic bandages for symptomatic relief in acute DVT, either iliofemoral, popliteal or calf; 2-thigh-length GCS (30-40 mmHg at the ankle) after ilio-femoral DVT; 3- knee-length GCS (30-40 mmHg at the ankle) after popliteal DVT; 4-GCS for different length of times according to the severity of periodically assessed PTS; 5-catheter-directed thrombolysis, with or without mechanical thrombectomy, in patients with iliofemoral obstruction, severe symptoms, and low risk of bleeding. The items rated as appropriate for treatment were: 1- thigh-length GCS (30-40 mmHg at the ankle) after iliofemoral DVT; 2-compression therapy for ulcer treatment; 3- exercise training. The role of endovascular treatment (angioplasty and/or stenting) was rated as uncertain, but it could be considered for severe PTS only in case of stenosis or occlusion above the inguinal ligament, followed by oral anticoagulation. Conclusions and Relevance: This position paper can help practicing clinicians in PTS management.

Long-Term Risk for Major Bleeding During Extended Oral Anticoagulant Therapy for First Unprovoked Venous Thromboembolism : A Systematic Review and Meta-analysis.

BACKGROUND: The long-term risk for major bleeding in patients receiving extended (beyond the initial 3 to 6 months) anticoagulant therapy for a first unprovoked venous thromboembolism (VTE) is uncertain. PURPOSE: To determine the incidence of major bleeding during extended anticoagulation of up to 5 years among patients with a first unprovoked VTE, overall, and in clinically important subgroups. DATA SOURCES: MEDLINE, Embase, and the Cochrane Central Register of Controlled Trials from inception to 23 July 2021. STUDY SELECTION: Randomized controlled trials (RCTs) and prospective cohort studies reporting major bleeding among patients with a first unprovoked VTE who were to receive oral anticoagulation for a minimum of 6 additional months after completing at least 3 months of initial anticoagulant treatment. DATA EXTRACTION: Two reviewers independently abstracted data and assessed study quality. Unpublished data required for analyses were obtained from authors of included studies. DATA SYNTHESIS: Among the 14 RCTs and 13 cohort studies included in the analysis, 9982 patients received a vitamin K antagonist (VKA) and 7220 received a direct oral anticoagulant (DOAC). The incidence of major bleeding per 100 person-years was 1.74 events (95% CI, 1.34 to 2.20 events) with VKAs and 1.12 events (CI, 0.72 to 1.62 events) with DOACs. The 5-year cumulative incidence of major bleeding with VKAs was 6.3% (CI, 3.6% to 10.0%). Among patients receiving either a VKA or a DOAC, the incidence of major bleeding was statistically significantly higher among those who were older than 65 years or had creatinine clearance less than 50 mL/min, a history of bleeding, concomitant use of antiplatelet therapy, or a hemoglobin level less than 100 g/L. The case-fatality rate of major bleeding was 8.3% (CI, 5.1% to 12.2%) with VKAs and 9.7% (CI, 3.2% to 19.2%) with DOACs. LIMITATION: Data were insufficient to estimate incidence of major bleeding beyond 1 year of extended anticoagulation with DOACs. CONCLUSION: In patients with a first unprovoked VTE, the long-term risks and consequences of anticoagulant-related major bleeding are considerable. This information will help inform patient prognosis and guide decision making about treatment duration for unprovoked VTE. PRIMARY FUNDING SOURCE: Canadian Institutes of Health Research. (PROSPERO: CRD42019128597).

Long-term risk of recurrent venous thromboembolism among patients receiving extended oral anticoagulant therapy for first unprovoked venous thromboembolism: A systematic review and meta-analysis.

BACKGROUND: The long-term risk for recurrent venous thromboembolism (VTE) during extended anticoagulation for a first unprovoked VTE is uncertain. OBJECTIVES: To determine the incidence of recurrent VTE during extended anticoagulation of up to 5 years in patients with a first unprovoked VTE. METHODS: MEDLINE, EMBASE, and the Cochrane CENTRAL were searched to identify randomized trials and prospective cohort studies reporting recurrent VTE among patients with a first unprovoked VTE who were to receive anticoagulation for a minimum of six additional months after completing ≥3 months of initial treatment. Unpublished data on number of recurrent VTE and person-years, obtained from authors of included studies, were used to calculate study-level incidence rate, and random-effects meta-analysis was used to pool results. RESULTS: Twenty-six studies and 15 603 patients were included in the analysis. During 11 631 person-years of follow-up, the incidence of recurrent VTE and fatal pulmonary embolism per 100 person-years was 1.41 (95% CI, 1.03-1.84) and 0.09 (0.04-0.16), with 5-year cumulative incidences of 7.1% (3.0%-13.2%) and 1.2% (0.4%-4.6%), respectively. The incidence of recurrent VTE was 1.08 (95% CI, 0.77-1.44) with direct oral anticoagulants and 1.55 (1.01-2.20) with vitamin K antagonists. The case-fatality rate of recurrent VTE was 4.9% (95% CI, 2.2%-8.7%). CONCLUSIONS: In patients with a first unprovoked VTE, the long-term risk of recurrent VTE during extended anticoagulation is low but not negligible. Thus, clinicians and patients should be aware of this risk and take appropriate and timely action in case of suspicion of recurrent VTE. Estimates from this study can be used to advise patients on what to expect while receiving extended anticoagulation, and estimate the net clinical benefit of extended treatment to guide long-term management of unprovoked VTE.

Management and Outcomes of Isolated Distal Deep Vein Thromboses: A Questionable Trend toward Long-Lasting Anticoagulation Treatment. Results from the START-Register.

Background Isolated distal deep vein thromboses (IDDVT) are frequently diagnosed; however, their natural history and real risk of complications are still uncertain. Though treatment is still not well standardized, international guidelines recommend no more than 3 months of anticoagulation therapy. We investigated how Italian clinicians treat IDDVT patients in their real life in our country. Methods Baseline characteristics and clinical history of the patients enrolled in the prospective, observational, multicenter START-Register for a first IDDVT or proximal DVT (PDVT) were analyzed. Results Overall, 412 IDDVT patients were significantly younger, with better renal function, and more frequent major transient risk factors, when compared with 1,173 PDVT patients. The anticoagulation duration was >180 days in 52.7% of IDDVT patients (70.7% in PDVT). During treatment, bleeding occurred in 5.6 and 2.8% patient-years in IDDVT and PDVT, respectively ( p = 0082). Bleeding was more frequent in IDDVT than PDVT patients treated with warfarin (6.8 vs. 3.2 patient-years, p = 0.0228, respectively). Thrombotic complications occurred in 1.1 and 2.4% patient-years in IDDVT and PDVT patients, respectively. Analyzing together the two groups, 66.1% of bleeds and 86.1% thrombotic complications occurred after 90 days anticoagulation treatment. Conclusion The large majority of IDDVT patients received anticoagulation for more than 3 months. Most bleeding and thrombotic complications occurred after the first 90 days of anticoagulation therapy. These results indicate that an extended anticoagulation beyond 90 days in IDDVT patients is associated with increased risk of complications. Whether an extended treatment may lower recurrences after anticoagulation withdrawal should be assessed by specifically designed studies.

Relevance of immobility as a risk factor for symptomatic proximal and isolated distal deep vein thrombosis in acutely ill medical inpatients.

Immobility is a well-recognized risk factor for deep vein thrombosis (DVT) in surgical patients, whereas the level of DVT risk conferred by immobility is less defined in patients on medical wards. The aim of this study was to establish whether immobility and its duration are associated with the risk of DVT in acutely ill medical inpatients. We conducted a cohort study in acutely ill medical inpatients. Patients underwent whole leg ultrasound for suspected lower extremity DVT and were divided into two groups according to presence or absence of immobility, defined as total bed rest or sedentary without bathroom privileges. The endpoint was the detection of proximal DVT or isolated distal DVT (IDDVT). Among the 252 acutely ill medical inpatients with immobility (age 82.6 ± 10.3 years, female 63.9%), ultrasound showed 36 (14.3%) proximal DVTs and 39 (15.5%) IDDVTs, while there were 11 (4.4%) proximal DVTs and 26 (10.5%) IDDVTs among the 248 inpatients without immobility (age 73.6 ± 14.2 years, female 54.8%). The risk of proximal DVT was higher in immobile than in mobile patients (OR 3.59, 95% CI: 1.78-7.23, p = 0.0001), whereas the risk of IDDVT was similar between the two groups (OR 1.56, 95% CI: 0.92-2.66, p = 0.111). During the first 3 days of hospitalization, the frequency of all DVTs was similar in patients with and without immobility, but it was 0.26 ± 0.03 vs 0.18 ± 0.03, respectively, after 4 days. In conclusion, immobility for more than 3 days is a risk factor for proximal DVT in acutely ill medical inpatients.

Heparin-induced thrombocytopenia and COVID-19.

Heparin-induced thrombocytopenia (HIT) has not been included as a possible cause of thrombocytopenia in Coronavirus Disease 2019 (COVID-19) patients. We report a case of HIT in a patient with COVID-19 treated with heparin. A 78-yearold man was admitted to our hospital for acute respiratory failure and acute renal failure due to SARS-CoV-2 infection; in intensive care unit, one 5000IU heparin dose (day 0, platelet count 305000/µL). On day 2, haemoglobin started to decrease and heparin was stopped. On day 10, platelet count was 153000/µL and 5000IU calcium heparin subcutaneously twice daily was started. The platelet further decreased, reaching 49000/µL on day 17, and the patient was investigated for suspected HIT: an IgG specific chemiluminescence test for heparin- PF4 antibodies was positive and a femoral DVT was found at ultrasound. Argatroban was started, platelet count increased without any bleeding and thrombosis complication. Our experience shows that HIT may develop in heparin treated COVID-19 patients and should be included among the possible cause of thrombocytopenia in such patients.

Thrombophilia testing in the real-world clinical setting of thrombosis centres taking part in the Italian Start 2-Register.

BACKGROUND: Even though it rarely influences venous thromboembolism (VTE) treatment and the fact that it is generally discouraged, thrombophilia testing is still largely prescribed. We assessed: 1) whether/how frequently Italian thrombosis centres requested thrombophilia testing; 2) what results were obtained; and 3) if the results affected treatment and clinical results. MATERIALS AND METHODS: We examined data from 4,826 VTE patients enrolled by 19 clinical centres participating in the START 2-Register. RESULTS: 57.2% of patients were tested. Numbers varied widely among centres (2.9-99.7%). Thrombophilic alterations were recorded in 18.2% of patients and the percentage of positive results was inversely correlated with that of patients tested. Significantly less patients with deep vein thrombosis (DVT) were tested, whereas more were tested when the event was idiopathic, presenting as isolated pulmonary embolism (PE), or in unusual sites. Patients with thrombophilic alterations were younger, more frequently treated with direct oral anticoagulants (DOACs), with lower mortality and less frequently discontinued anticoagulation. DOACs were more frequently prescribed in patients with heterozygous Factor V (FV) Leiden or prothrombin mutations, whereas vitamin K antagonists were preferred in patients with inhibitor deficiencies, combined alterations or antiphospholipid syndrome (APLS). There was no difference in duration of treatment among those with or without alterations, though more APLS patients received an extended treatment course. Bleeding and thrombotic complications occurred with a similar and fairly low incidence in patients with or without thrombophilic alterations. DISCUSSION: Although general testing for thrombophilia in VTE patients is currently discouraged, more than half of the VTE patients included in the START2-Register were tested. However, there were marked differences in practice between Italian thrombosis centres. About 60% of all patients with alterations were treated with DOACs, confirming that DOACs can be a useful option for treatment of thrombophilic VTE patients, with the exclusion of those with APLS.