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.
Introduction Anticoagulation monitoring is a major practical and clinical challenge. We assessed the performance of the microINR system in patient self-testing (PST). Methods This study was performed at four US medical centers. After the training visit of warfarin anticoagulated patients ( n = 117) on microINR system, PST was performed at home and in two visits to the medical centers. At the medical centers, both PST and healthcare professionals (HCPs) performed duplicate tests with the microINR System. A venous blood sample for the laboratory testing was also extracted. Accuracy and precision were assessed. Results The comparison between microINR PST results and microINR HCP results revealed an equivalence with a slope of 1.00 (95% confidence interval [CI]: 1.00-1.00), and an intercept of 0.00 (95% CI: 0.00-0.00). When compared with the laboratory analyzer, microINR PST results also showed good correlation with a slope of 0.94 (95% CI: 0.86-1.04) and an intercept of 0.14 (95% CI: -0.09-0.34). Predicted bias values at international normalized ratio (INR) 2.0, 3.5, and 4.5 were 0% against HCP and ≤2.5% against the laboratory. Analytical agreement with both HCP and laboratory was 100% according to ISO17593 and 99.1 and 100% according to CLSI POCT14 with HCP and laboratory, respectively. Clinical agreement with HCP regarding 2.0-4.0 as INR therapeutic range was 98% (within range). The precision (coefficient of variation) of microINR system used by PST was comparable to HCP. Conclusion The microINR results when used by self-testing patients show satisfactory concordance to both HCP results and laboratory analyzer. The microINR system is adequate for self-testing use.
Coagulation factor X (FX), often termed as Stuart-Prower factor, is a plasma glycoprotein composed of the γ-carboxyglutamic acid (GLA) domain, two epidermal growth factor domains (EGF-1 and EGF-2), and the serine protease (SP) domain. FX plays a pivotal role in the coagulation cascade, activating thrombin to promote platelet plug formation and prevent excess blood loss. Genetic variants in FX disrupt coagulation and lead to FX or Stuart-Prower factor deficiency. To better understand the relationship between FX deficiency and disease severity, an interactive FX variant database has been set up at https://www.factorx-db.org , based on earlier web sites for the factor-XI and -IX coagulation proteins. To date (April 2021), we report 427 case reports on FX deficiency corresponding to 180 distinct F10 genetic variants. Of these, 149 are point variants (of which 128 are missense), 22 are deletions, 3 are insertions, and 6 are polymorphisms. FX variants are phenotypically classified as being type I or II. Type-I variants involve the simultaneous reduction of FX coagulant activity (FX:C) and FX antigen levels (FX:Ag), whereas type-II variants involve a reduction in FX:C with normal FX:Ag plasma levels. Both types of variants were distributed throughout the FXa protein structure. Analyses based on residue surface accessibilities showed the most damaging variants to occur at residues with low accessibilities. The interactive FX web database provides a novel easy-to-use resource for clinicians and scientists to improve the understanding of FX deficiency. Guidelines are provided for clinicians who wish to use the database for diagnostic purposes.
Background Direct-acting oral anticoagulants (DOACs) do not require monitoring. Measurement of DOAC effect would be useful in the event of bleeding, trauma, and thromboembolism while on anticoagulation. We evaluated the effectiveness of the investigational DOAC assays on the TEG®6s Hemostasis Analyzer to assess the anticoagulant effect of DOACs in patients treated for atrial fibrillation or deep vein thrombosis (DVT). Methods Patients on treatment for a minimum of 7 days with standard doses of dabigatran, rivaroxaban, and apixaban were included. DOAC plasma concentrations and TEG®6s Reaction (R)-time were measured and correlated. The sensitivity, specificity, and negative predictive value (NPV) of R-time to detect DOAC concentrations of ≥30, ≥50, and ≥100 ng/mL were calculated. Results A total of 189 patients were included, ( n = 50) on apixaban, ( n = 62) on rivaroxaban, ( n = 53) on dabigatran, and ( n = 24) on no DOAC were studied. Using the direct thrombin inhibitor (DTI) channel, R-time demonstrated strong linear correlation with dabigatran levels (r = 0.93, p < 0.0001). Using the antifactor Xa (AFXa) channel, R-time demonstrated strong nonlinear correlation with rivaroxaban and apixaban levels ( r s = 0.92 and 0.84, respectively, p < 0.0001 for both). R-time revealed strong sensitivity and NPV in detecting low DOAC levels for the predefined concentrations. Conclusion R-time measured by TEG®6s DOAC-specific cartridge has a strong correlation with concentrations of the most commonly used DOACs with high sensitivity and NPV for detecting lower drug levels that are considered clinically relevant for patients in need of antidote, or prior to urgent surgery. Further studies to determine the relation of R-time to clinical outcomes are warranted.
Background Single nucleotide polymorphisms (SNPs) in vascular endothelial growth factor A ( VEGFA ) are associated with susceptibility to several diseases including cancer. Correlations between VEGFA rs3025020 genotypes with clinical and laboratory features of primary myelofibrosis (PMF) are unstudied. Methods DNA was analyzed by real-time polymerase chain reaction for VEGFA rs3025020 genotypes in a cohort of 844 subjects with PMF and in two cohorts of normal subjects ( N = 247 and N = 107). Results Frequency of rs3025020 minor allele (T) was not significantly different in subjects with PMF compared with normals; however, the T-allele was more frequent in PMF subjects with a calreticulin ( CALR )-mutated genotype compared with normals (35 vs. 27%; OR = 1.47 [95% CI, 1.09, 1.98] p = 0.011), especially in subjects with a CALR- type 2/type 2-like mutation (43 vs. 27%; OR = 2.01 [1.25, 3.24] p = 0.004). CALR mutants with the rs3025020 TT genotype had higher CXCR4 expression on CD34-positive blood cells, and those who carried CT/TT genotypes had lower platelet concentrations compared with other genotypes at diagnosis. Overall, subjects with the rs3025020 CT/TT genotype had a lower cumulative incidence of deep vein thrombosis in typical sites (1.6 vs. 4.2%; OR = 0.37 [0.15, 0.90] p = 0.029) and longer interval from diagnosis to first thrombosis (HR = 0.37 [0.14, 0.95] p = 0.039). Conclusion Persons with PMF and the VEGFA rs3025020 minor T-allele are more likely to have a CALR mutation compared with other somatic driver mutations and lower cumulative incidence and hazard for deep vein thrombosis in typical sites.
Background Cardiovascular benefits of aggressive dual antiplatelet therapy may be associated with extra risks including bleeding, cancer, and infections discovered first for prasugrel in the TRial to assess Improvement in Therapeutic Outcomes by optimizing platelet InhibitioN with prasugrel (TRITON) trial. Ticagrelor in PLATO also caused slightly more infections but surprisingly less sepsis-related deaths (SRD) than clopidogrel. However, verified infection fatalities in PLATO were lacking from the public domain. We obtained the complete Food and Drug Administration (FDA)-issued primary causes death list, matched it with the few local site records dataset and analyzed the patterns of infections and deaths reported in PLATO. Methods Among infections, the FDA spreadsheet contains only two primary death codes for pneumonia (12-2) and SRD (12-8). We obtained local evidence for two pneumonia and two SRD and matched those with the FDA records. We assessed how SRD patterns were reported among nonvascular death's dataset. Results The FDA PLATO records indicate that clopidogrel caused numerically less ( n = 8) primary pneumonia deaths than ticagrelor ( n = 10) but over three times more SRD ( n = 23/7). Among matched verifiable outcomes, both pneumonia deaths were correct, but two clopidogrel SRD were incorrect. Of the remaining 21 clopidogrel SRD, 6 were reported as two separate closed paired entries in Brazil (lines 76 and 78 and 86 and 88) and India (lines 436 and 440), suggesting last minute addition of potentially incorrect SRD reports. Four ticagrelor SRD (lines 24,193,467 and 650) were "compensated" with close or next in line clopidogrel SRD entries (lines 22,195,468 and 651). Conclusion The FDA-issued evidence suggests no benefit of ticagrelor in preventing deaths from infections with slightly more pneumonia deaths, with possible misreporting of SRD in PLATO. These findings require an in-depth precise review of sepsis deaths in this trial.
Coagulation Factor XI (FXI) is a plasma glycoprotein composed of four apple (Ap) domains and a serine protease (SP) domain. FXI circulates as a dimer and activates Factor IX (FIX), promoting thrombin production and preventing excess blood loss. Genetic variants that degrade FXI structure and function often lead to bleeding diatheses, commonly termed FXI deficiency. The first interactive FXI variant database underwent initial development in 2003 at https://www.factorxi.org . Here, based on a much improved FXI crystal structure, the upgraded FXI database contains information regarding 272 FXI variants (including 154 missense variants) found in 657 patients, this being a significant increase from the 183 variants identified in the 2009 update. Type I variants involve the simultaneous reduction of FXI coagulant activity (FXI:C) and FXI antigen levels (FXI:Ag), whereas Type II variants result in decreased FXI:C yet normal FXI:Ag. The database updates now highlight the predominance of Type I variants in FXI. Analysis in terms of a consensus Ap domain revealed the near-uniform distribution of 81 missense variants across the Ap domains. A further 66 missense variants were identified in the SP domain, showing that all regions of the FXI protein were important for function. The variants clarified the critical importance of changes in surface solvent accessibility, as well as those of cysteine residues and the dimer interface. Guidelines are provided below for clinicians who wish to use the database for diagnostic purposes. In conclusion, the updated database provides an easy-to-use web resource on FXI deficiency for clinicians.
Protein S (PS) deficiency is a risk factor for venous thromboembolism (VTE) and can be caused by variants of the gene encoding PS ( PROS1 ). This study aimed to evaluate the clinical value of molecular analysis of the PROS1 gene in PS-deficient participants. We performed Sanger sequencing of the coding region of the PROS1 gene and multiplex ligation-dependent probe amplification to exclude large structural rearrangements. Free PS was measured by a particle-enhanced immunoassay, while PS activity was assessed by a clotting method. A total of 87 PS-deficient participants and family members were included. In 22 index participants, we identified 13 PROS1 coding variants. Five variants were novel. In 21 index participants, no coding sequence variants or structural rearrangements were identified. The free PS level was lower in index participants carrying a PROS1 variant compared with index participants with no variant (0.51 [0.32-0.61] vs. 0.62 [0.57-0.73] × 10 3 IU/L; p < 0.05). The p.(Thr78Met) variant was associated with only slightly decreased free PS levels (0.59 [0.53-0.66] × 10 3 IU/L) compared with the p.(Glu390Lys) variant (0.27 [0.24-0.37] × 10 3 IU/L, p < 0.01). The frequency of VTE in participants with a coding PROS1 variant was 43 and 17% in the group with normal PROS1 gene ( p = 0.05). In conclusion, we report 13 PROS1 coding variants including five novel variants. PS levels differ by PROS1 variant and the frequency of VTE was higher when a coding PROS1 variant was present. Hence, molecular analysis of the PROS1 gene may add clinical value in the diagnostic work-up of PS deficiency.
The cause of atherothrombosis is rupture or erosion of atherosclerotic lesions, leading to an increased risk of myocardial infarction or stroke. Here, platelet activation plays a major role, leading to the release of bioactive molecules, for example, chemokines and coagulation factors, and to platelet clot formation. Several antiplatelet therapies have been developed for secondary prevention of cardiovascular events, in which anticoagulant drugs are often combined. Besides playing a role in hemostasis, platelets are also involved in inflammation. However, it is unclear whether current antiplatelet therapies also affect platelet immune functions. In this study, the possible anti-inflammatory effects of antiplatelet medications on chemokine release were investigated using enzyme-linked immunosorbent assay and on the chemotaxis of THP-1 cells toward platelet releasates. We found that antiplatelet medication acetylsalicylic acid (ASA) led to reduced chemokine (CC motif) ligand 5 (CCL5) and chemokine (CXC motif) ligand 4 (CXCL4) release from platelets, while leukocyte chemotaxis was not affected. Depending on the agonist, α IIb β 3 and P2Y 12 inhibitors also affected CCL5 or CXCL4 release. The combination of ASA with a P2Y 12 inhibitor or a phosphodiesterase (PDE) inhibitor did not lead to an additive reduction in CCL5 or CXCL4 release. Interestingly, these combinations did reduce leukocyte chemotaxis. This study provides evidence that combined therapy of ASA and a P2Y 12 or PDE3 inhibitor can decrease the inflammatory leukocyte recruiting potential of the releasate of activated platelets.
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