TH Open: Companion Journal to Thrombosis and Haemostasis最新文献

Antiphospholipid syndrome (APS) is a systemic autoimmune disease characterized by arterial and venous thrombotic manifestations and/or pregnancy-related complications in patients with persistent antiphospholipid (aPL) antibodies. The introduction of Sapporo's classification criteria allowed uniformity in the classification of this pathology, representing a considerable advance in its diagnosis. However, currently some doubts about the application of these criteria still persist. The aim of this study was to contribute to the better understanding of APS by the assessment of aPL prevalence, the association between clinical and laboratory tests, and evaluation of the aPL confirmatory profile. In this study, 1,179 samples from patients with suspected APS of both genders, without age restrictions, who were advised to test for complete aPL's profile were analyzed. The samples were tested for lupus anticoagulant (LAC), anticardiolipin immunoglobulin (Ig) G/IgM and anti-β-2-glycoprotein I IgG/IgM antibodies. Patient samples with isolated test requests for analysis and samples from patients under the influence of anticoagulants or in an infectious process were excluded. The overall positivity found was 17.9% and the most frequent aPL was LAC. The antibodies were determined in isolation and in association. The prevalence of triple positivity was 0.8% and double positivity was 1.8%. Positivity was higher in inpatient/emergency services compared with outpatient services. There was a higher positivity in individuals over 41 years, males, patients with systemic lupus erythematosus, kidney complications, and deep vein thrombosis/thrombophlebitis. The positivity confirmation with second sample was 39.5% and the confirmation profile shows that 50.6% of samples confirmed with same positivity profile; 17.3% with a different profile and regarding to these, 2.5% of the samples confirmed positivity with a different antibody from the previously detected. This study suggests that the aPL's positivity tends to increase with age, showing that the aPL's testing should be avoided during an acute event and reinforces the need for complete aPL laboratory profile in the second sample and subsequent determinations.

Background  The efficacy and safety of rivaroxaban have been demonstrated in phase 3 trials of patients with venous thromboembolism (VTE; pulmonary embolism [PE] and deep vein thrombosis [DVT]). Data regarding rivaroxaban treatment of VTE in routine Japanese clinical practice remain limited. Objectives  XASSENT will evaluate rivaroxaban treatment of VTE in real-world Japanese clinical practice. We report the study design and baseline patient characteristics. Methods  XASSENT (NCT02558465) is an open-label, prospective observational, post-marketing surveillance cohort study in patients receiving rivaroxaban treatment for VTE. Enrolment took place between November 2015 and March 2018. XASSENT will follow patients for up to 2 years. Primary outcome variables: major bleeding and symptomatic recurrent VTE. Statistical analyses are exploratory and descriptive. Results  Baseline patient characteristics at June 2020 ( n  = 2,299) are presented (58.2% female; mean age 66.7 years; mean weight 60.9 kg). The population encompasses patients with wide-ranging characteristics including older age, low weight, and renal dysfunction. Most participants (67.6%) had a history of VTE risk factors at baseline. Half of the population (50.4%) had DVT only; 41.4% had DVT with PE; 8.2% had PE only. Overall, 68.4% were inpatients and 77.1% had symptomatic VTE. Rivaroxaban was prescribed for initial treatment in 84.6% of patients and maintenance treatment in 15.4%. Most were prescribed the approved dose of rivaroxaban for initial (30 mg daily; 84.4%) or maintenance (15 mg daily; 81.9%) treatment of VTE in Japan. The most common reason for selecting non-recommended dose was 'elderly'. Conclusions  Results from XASSENT will complement phase 3 trial data and inform clinical practice.

Background  Patients undergoing systemic cancer therapy are susceptible to developing venous thromboembolism (VTE). The most pertinent prognostic factors for VTE remain unclear. This systematic review aims to summarize prognostic factors associated with VTE in this population. Methods  MEDLINE, Embase, and CENTRAL databases were searched for observational or randomized studies that used multivariable analysis adjusted for tumor type and/or metastatic disease to model the risk of VTE. Adjusted effect estimates for each prognostic factor were collected for all of the included studies. Risk of bias was assessed using the Quality in Prognostic Factor Studies (QUIPS) tool. Results  From 5,988 search results, 15 eligible studies and 42 prognostic factors were identified. A total of 8,554 patients of whom 456 (5.33%) developed VTE were included. Fourteen studies had a high risk of bias and one study had a moderate risk. The most commonly reported prognostic factors include age, gender, tumor site, metastasis, performance status, and systemic therapy type. Poor performance status and the use of platinum-based chemotherapy compounds were associated with an increased risk of VTE across the majority of studies. The evidence to suggest that the other prognostic factors identified were associated with VTE development was inconclusive. Several individual studies identified novel biomarkers for VTE. Heterogeneity in statistical methods and prognostic factor definitions across studies precluded meta-analysis. Conclusion  Overall, many prognostic factors were identified; however, the evidence for association with development of VTE for most of the factors is inconclusive. Findings were limited by high heterogeneity and risk of bias in the included studies.

Introduction  Prehospital therapy of ST-elevation myocardial infarction (STEMI) with αIIbβ3 antagonists improves clinical outcomes, but they are difficult to use in prehospital settings. RUC-4 is a novel αIIbβ3 antagonist being developed for prehospital therapy of STEMI that rapidly achieves high-grade platelet inhibition after subcutaneous administration. Standard light transmission aggregometry (LTA) is difficult to perform during STEMI, so we applied VerifyNow (VN) assays to assess the pharmacodynamics of RUC-4 relative to aspirin and ticagrelor. Methods  Blood from healthy volunteers was anticoagulated with phenylalanyl-prolyl-arginyl chloromethyl ketone (PPACK) or sodium citrate, treated in vitro with RUC-4, aspirin, and/or ticagrelor, and tested with the VN ADP + PGE ₁ , iso-TRAP, and base channel (high concentration iso-TRAP + PAR-4 agonist) assays. The results were correlated with both ADP (20 µM)-induced LTA and flow cytometry measurement of receptor occupancy and data from individuals treated in vivo with RUC-4. Results  RUC-4 inhibited all three VN assays, aspirin did not affect the assays, and ticagrelor markedly inhibited the ADP + PGE ₁ assay, slightly inhibited the iso-TRAP assay, and did not inhibit the base channel assay. RUC-4's antiplatelet effects were potentiated in citrate compared with PPACK. Cut-off values were determined to correlate the results of the VN iso-TRAP and base channel assays with 80% inhibition of LTA. Conclusion  The VN assays can differentiate the early potent anti-αIIbβ3 effects of RUC-4 from delayed effects of P2Y12 antagonists in the presence of aspirin. These pharmacodynamic assays can help guide the clinical development of RUC-4 and potentially be used to monitor RUC-4's effects in clinical practice.

Background and Purpose  Previous studies suggest an association between increased homocysteine (Hcy) and risk of ischemic stroke. Yet, it remains unknown whether a dose-response association exists between Hcy levels and risk of ischemic stroke. Methods  Systematic literature searches were performed in PubMed, Embase, Scopus, and Web of Science. Inclusion criteria were studies investigating ischemic stroke risk in an adult population with measured Hcy levels. We computed odds ratios (ORs) for a 5 µmol/L increase in Hcy levels using a random effects meta-analysis. Results  In total, 108 studies met the inclusion criteria of which 22 were rated as high-quality studies, and 20 studies included a dose-response analysis. Hcy levels were analyzed either as a continuous or categorical variable. The majority of the studies found an increased risk of ischemic stroke when comparing the highest-to-lowest Hcy strata. A graded association was observed over the Hcy strata, indicating a dose-response association, with the most apparent effect when Hcy levels exceeded approximately 15 µmol/L. No studies explored a potential nonlinear association between Hcy levels and ischemic stroke. Six studies were included in a meta-analysis, showing an OR of 1.43 (95% confidence interval [CI]: 1.28-1.61) per 5 µmol/L increase in Hcy levels. Conclusion  This review and meta-analysis indicate a dose-response association between Hcy levels and ischemic stroke. An evident increase in effect measures was observed when Hcy levels exceeded 15 µmol/L, indicating a nonlinear association between ischemic stroke and Hcy levels. This nonlinear association warrants further study. This study is registered with clinical trial ( https://www.crd.york.ac.uk/prospero/ ; unique identifier: CRD42019130371).

The DOAC Dipstick accurately detects the presence or absence of factor Xa (DXI) and thrombin inhibitor (DTI) classes of direct oral anticoagulants (DOACs) in patients' urine samples on DOAC treatment. The aim of the study was to systematically review the literature and compare the performance of prototype and commercial test strips with a meta-analysis. A systematic literature search of electronic databases PubMed (MEDLINE) and Cochrane Library was performed. Heterogeneity between studies was calculated using the Chi-squared test and the I ² index. A random effects model was used to pool data to compare the performance of prototype and commercial test strips. Using PRISMA reporting guidelines, four of 1,081 publications were eligible for inclusion in the meta-analysis: three reporting on prototype (DXI n  = 658, DTI n  = 586) and one on commercial test strips (DXI n  = 451, DTI n  = 429). Sensitivity and specificity of DXI and DTI detection did not differ significantly between the prototype and commercial test strips. Odds ratios were 0.718 and 0.365 for sensitivity and 1.211 and 1.072 for specificity of DXI and DTI (p-values between 0.3334 and 1.000), respectively. The pooled sensitivity and specificity values for DXI were 0.968 ( p  = 0.1290, I ² 47.1%) and 0.979 ( p  = 0.1965, I ² 35.9%), and for DTI 0.993 ( p  = 0.1870, I ² 37.5%) and 0.993 ( p  = 0.7380, I ² 0%), respectively. Prototype and commercial DOAC test strips did not differ in their ability to detect DXI and DTI in patient urine samples. This supports the confidence in use of the DOAC Dipstick test, although it needs to be validated in specific patient populations.

Laboratory confirmation of heparin-induced thrombocytopenia (HIT) is of crucial importance and remains challenging and relies on platelet functional assays highlighting the presence of heparin-dependent platelet-activating antibodies in patient serum or plasma. Platelet functional assays using washed platelets include the ¹⁴ C-serotonin release assay (SRA), usually described as the gold standard, and the heparin-induced platelet activation assay (HIPA). Since its first comparison with SRA there has been no additional published study regarding HIPA diagnostic performances compared with SRA. Aim of our retrospective study was to compare the concordance between HIPA and SRA in HIT suspected-patients with positive anti-PF4/heparin antibodies between October 2010 and October 2015. Fifty-five HIT-suspected patients who beneficiated from both HIPA and SRA were included. Positive and negative percent agreements were 83.8% (95% CI 68.0-93.8%) and 66.7% (95% CI 41.0-86.7%), respectively. Overall percent agreement was 78.2% (95% CI 65.0-92.2%). Agreement was higher in patients who underwent cardiopulmonary bypass with extracorporeal circulation circuit for cardiac surgery. We also confirm that the use of a minimum of 2 platelet donors to establish positive HIT diagnosis and 4 platelet donors to exclude HIT diagnosis allows obtaining a good agreement with SRA. Although HIPA and SRA were performed with different platelet donors and in different laboratories, HIPA had a good positive agreement with SRA for HIT diagnosis, showing that HIPA is a useful functional assay that does not require radioactivity and could be developed worldwide to improve HIT diagnosis.

The global thrombosis test (GTT) is a point of care device that tests thrombotic and thrombolytic status. The device exposes whole blood flow to a combination of both high and low shear stress past and between ball bearings potentially causing thrombin and fibrin formation. The question arises as to whether thrombosis in the GTT is dominated by coagulation-triggered red clot or high shear-induced white clot. We investigated the nature of the thrombus formed in the GTT, the device efficacy, human factors use, and limitations. The GTT formed clots that were histologically fibrin-rich with trapped red blood cells. The occlusion time (OT) was more consistent with coagulation than high shear white clot and was strongly lengthened by heparin and citrate, two common anticoagulants. The clot was lysed by tissue plasminogen activator (tPA), also consistent with a fibrin-rich red clot. Changing the bead to a collagen-coated surface and eliminating the low shear zone between the beads induced a rapid OT consistent with a platelet-rich thrombus that was relatively resistant to heparin or tPA. The evidence points to the GTT as occluding primarily due to fibrin-rich red clot from coagulation rather than high shear platelet aggregation and occlusion associated with arterial thrombosis.

Background  Diagnostic strategies for suspected pulmonary embolism (PE) have not been prospectively evaluated in COVID-19 patients. Methods  Prospective, multicenter, outcome study in 707 patients with both (suspected) COVID-19 and suspected PE in 14 hospitals. Patients on chronic anticoagulant therapy were excluded. Informed consent was obtained by opt-out approach. Patients were managed by validated diagnostic strategies for suspected PE. We evaluated the safety (3-month failure rate) and efficiency (number of computed tomography pulmonary angiographies [CTPAs] avoided) of the applied strategies. Results  Overall PE prevalence was 28%. YEARS was applied in 36%, Wells rule in 4.2%, and "CTPA only" in 52%; 7.4% was not tested because of hemodynamic or respiratory instability. Within YEARS, PE was considered excluded without CTPA in 29%, of which one patient developed nonfatal PE during follow-up (failure rate 1.4%, 95% CI 0.04-7.8). One-hundred seventeen patients (46%) managed according to YEARS had a negative CTPA, of whom 10 were diagnosed with nonfatal venous thromboembolism (VTE) during follow-up (failure rate 8.8%, 95% CI 4.3-16). In patients managed by CTPA only, 66% had an initial negative CTPA, of whom eight patients were diagnosed with a nonfatal VTE during follow-up (failure rate 3.6%, 95% CI 1.6-7.0). Conclusion  Our results underline the applicability of YEARS in (suspected) COVID-19 patients with suspected PE. CTPA could be avoided in 29% of patients managed by YEARS, with a low failure rate. The failure rate after a negative CTPA, used as a sole test or within YEARS, was non-negligible and reflects the high thrombotic risk in these patients, warranting ongoing vigilance.

Background  Dentoalveolar procedures in immune thrombocytopenia (ITP) pose a risk of bleeding due to thrombocytopenia and infection due to immunosuppressive treatments. We aimed to systematically review the safety and management of dentoalveolar procedures in ITP patients to create practical recommendations. Methods  PubMed, Embase, Cochrane, and Cinahl were searched for original studies on dentoalveolar procedures in primary ITP patients. We recorded bleeding- and infection-related outcomes and therapeutic strategies. Clinically relevant bleeding was defined as needing medical attention. Results  Seventeen articles were included, of which 12 case reports/series. Overall, the quality of the available evidence was poor. Outcomes and administered therapies (including hemostatic therapies and prophylactic antibiotics) were not systematically reported. At least 73 dentoalveolar procedures in 49 ITP patients were described. The range of the preoperative platelet count was 2 to 412 × 10 ⁹ /L. Two clinically relevant bleedings (2%) were reported in the same patient of which one was life-threatening. Strategies used to minimize the risk of bleeding were heterogeneous and included therapies to increase platelet count, antifibrinolytics, local measures, and minimally invasive techniques. Reports on the occurrence of bleedings due to anesthetics or infection were lacking. Conclusion  Based on alarmingly limited data, clinically relevant bleedings and infections after dentoalveolar procedures in ITP patients seem rare. Awaiting prospective and controlled studies to further evaluate these risks and the efficacy of therapeutic interventions, we provided our institutional guideline to guide the management of dentoalveolar procedures in ITP patients.