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

The vascular obstructive thrombus is composed of a mesh of fibrin fibers with blood cells trapped in these networks. Enhanced fibrin clot formation and/or suppression of fibrinolysis are associated with an increased risk of vascular occlusive events. Inhibitors of coagulation factors and activators of plasminogen have been clinically used to limit fibrin network formation and enhance lysis. While these agents are effective at reducing vascular occlusion, they carry a significant risk of bleeding complications. Fibrin clot lysis, essential for normal hemostasis, is controlled by several factors including the incorporation of antifibrinolytic proteins into the clot. Plasmin inhibitor (PI), a key antifibrinolytic protein, is cross-linked into fibrin networks with higher concentrations of PI documented in fibrin clots and plasma from high vascular risk individuals. This review is focused on exploring PI as a target for the prevention and treatment of vascular occlusive disease. We first discuss the relationship between the PI structure and antifibrinolytic activity, followed by describing the function of the protein in normal physiology and its role in pathological vascular thrombosis. Subsequently, we describe in detail the potential use of PI as a therapeutic target, including the array of methods employed for the modulation of protein activity. Effective and safe inhibition of PI may prove to be an alternative and specific way to reduce vascular thrombotic events while keeping bleeding risk to a minimum. Key Points Plasmin inhibitor (PI) is a key protein that inhibits fibrinolysis and stabilizes the fibrin network.This review is focused on discussing mechanistic pathways for PI action, role of the molecule in disease states, and potential use as a therapeutic target.

Purpose  We investigated the 1-year risk of stroke in patients with retinal artery occlusion and evaluated the predictive and discriminating abilities of contemporary risk stratification models for embolic stroke. Methods  This register-based cohort study included 7,906 patients with retinal artery occlusion from Danish nationwide patient registries between 1995 and 2018. The study population was stratified according to the number of points obtained in the stroke risk scores: the CHA ₂ DS ₂ -VASc score and the ESSEN Stroke Risk score. The 1-year risk of stroke within strata was evaluated and compared using the cox proportional hazards model. Furthermore, the discrimination of the risk scores as predictive tools for stroke risk assessment was investigated using C-statistics, Brier score, and the index of prediction accuracy. Results  The stroke event rate in patients with retinal artery occlusion increased as the score increased for both risk scores, ranging from 3.62 (95% confidence interval [CI]: 2.46-5.31) per 100 person-years to 13.25 (95% CI: 11.78--14.89) per 100-person-years for increasing levels of the CHA ₂ DS ₂ -VASc score and from 3.97 (95% CI: 2.97-5.32) per 100 person-years to 16.43 (95% CI: 14.01-19.27) per 100 person-years for increasing levels of the ESSEN Stroke Risk score. Using a risk score of 0 as a reference, the difference was statistically significant for retinal artery occlusion patients with a CHA ₂ DS ₂ -VASc score of 2 or above and for all levels of the ESSEN Stroke Risk score. The C-statistics for the risk scores was 61% (95% CI: 58%-63%) and 62% (95% CI: 59-64%) for the CHA ₂ DS ₂ -VASc score and ESSEN Stroke Risk score, respectively. Conclusion  The results suggested that the use of the CHA ₂ DS ₂ -VASc score and the ESSEN Stroke Risk score was applicable for risk stratification of stroke in patients with retinal artery occlusion, but discrimination was poor due to low specificity.

Glycoprotein (GP: HIS ¹ -PRO ²⁶⁵ ) Ibɑ is a receptor protein expressed on the surface of the platelet. Its N-terminus domain binds with the A1 domain (ASP ¹²⁶⁹ -PRO ¹⁴⁷² ) of its ligand protein von Willebrand factor (VWF) and plays a unique role in platelet adhesion under blood flow conditions. Single amino acid substitutions at residue 233 from glycine (G) to alanine (A), aspartic acid (D), or valine (V) are known to cause biochemically distinct functional alterations known as equal, loss, and gain of function, respectively. However, the underlying physical characteristics of VWF binding with GPIbɑ in wild-type and the three mutants exerting different biological functions are unclear. Here, we aimed to test the hypothesis: biological characteristics of macromolecules are influenced by small changes in physical parameters. The position coordinates and velocity vectors of all atoms and water molecules constructing the wild-type and the three mutants of GPIbɑ (G233A, G233D, and G233V) bound with VWF were calculated every 2 × 10 ^-15 seconds using the CHARMM (Chemistry at Harvard Macromolecular Mechanics) force field for 9 × 10 ^-10 seconds. Six salt bridges were detected for longer than 50% of the calculation period for the wild-type model generating noncovalent binding energy of -1096 ± 137.6 kcal/mol. In contrast, only four pairs of salt bridges were observed in G233D mutant with noncovalent binding energy of -865 ± 139 kcal/mol. For G233A and G233V, there were six and five pairs of salt bridges generating -929.8 ± 88.5 and -989.9 ± 94.0 kcal/mol of noncovalent binding energy, respectively. Our molecular dynamic simulation showing a lower probability of salt bridge formation with less noncovalent binding energy in VWF binding with the biologically loss of function G233D mutant of GPIbɑ as compared with wild-type, equal function, and gain of function mutant suggests that biological functions of macromolecules such as GPIbɑ are influenced by their small changes in physical characteristics.

Background  Compared with usual care, guideline-adherent stroke prevention strategy, based on the ABC (Atrial fibrillation Better Care) pathway, is associated with better outcomes. Given that stroke prevention is central to atrial fibrillation (AF) management, improved efforts to determining predictors of adherence with 'A' (avoid stroke) component of the ABC pathway are needed. Purpose  We tested the hypothesis that more sophisticated methodology using machine learning (ML) algorithms could do this. Methods  In this post-hoc analysis of the BALKAN-AF dataset, ML algorithms and logistic regression were tested. The feature selection process identified a subset of variables that were most relevant for creating the model. Adherence with the 'A' criterion of the ABC pathway was defined as the use of oral anticoagulants (OAC) in patients with AF with a CHA ₂ DS ₂ -VASc score of 0 (male) or 1 (female). Results  Among 2,712 enrolled patients, complete data on 'A'-adherent management were available in 2,671 individuals (mean age 66.0 ± 12.8; 44.5% female). Based on ML algorithms, independent predictors of 'A-criterion adherent management' were paroxysmal AF, center in capital city, and first-diagnosed AF. Hypertrophic cardiomyopathy, chronic kidney disease with chronic dialysis, and sleep apnea were independently associated with a lower likelihood of 'A'-criterion adherent management. ML evaluated predictors of adherence with the 'A' criterion of the ABC pathway derived an area under the receiver-operator curve of 0.710 (95%CI 0.67-0.75) for random forest with fine tuning. Conclusions  Machine learning identified paroxysmal AF, treatment center in the capital city, and first-diagnosed AF as predictors of adherence to the A pathway; and hypertrophic cardiomyopathy, chronic kidney disease with chronic dialysis, and sleep apnea as predictors of non adherence.

Introduction  Venous and arterial thromboses are frequently observed complications in patients with severe novel coronavirus disease 2019 (COVID-19) infection who require hospital admission. In this study, we evaluate the epidemiology of venous and arterial thrombosis events in ambulatory and postdischarge patients with COVID-19 infection. Materials and Method  EMBASE and MEDLINE were searched up to July 21, 2021, in addition to other sources. We included studies that assessed the epidemiology of venous and arterial thrombosis events in ambulatory and postdischarge COVID-19 patients. Results  A total of 16 studies (102,779 patients) were identified. The overall proportion of venous thromboembolic events in all patients, that is, ambulatory and postdischarge, was 0.80% (95% confidence interval [CI]: 0.44-1.28), 0.28% (95% CI: 0.07-0.64), and 1.16% (95% CI: 0.69-1.74), respectively. Arterial events occurred in 0.75% (95% CI: 0.27-1.47) of all patients, 1.45% (95% CI: 1.10-1.86) of postdischarge patients, and 0.23% (95% CI: 0.019-0.66) of ambulatory patients. The pooled incidence rate estimates per 1,000 patient-days for VTE events were 0.06 (95% CI: 0.03-0.08) and 0.12 (95% CI: 0.07-0.19) for outpatients and postdischarge, respectively, whereas for arterial events were 0.10 (95% CI: 0-0.30) and 0.26 (95% CI: 0.16-0.37). Conclusion  This study found a low risk of venous and arterial thrombi in ambulatory and postdischarge COVID-19 patients, with a higher risk in postdischarge patients compared with ambulatory patients. This suggests that regular universal thromboprophylaxis in these patient populations is probably not necessary.

Background  Coronavirus disease 2019 (COVID-19) infection causes acute respiratory insufficiency with severe interstitial pneumonia and extrapulmonary complications; in particular, it may predispose to thromboembolic disease. The reported incidence of thromboembolic complications varies from 5 to 30% of cases. Aim  We conducted a multicenter, Italian, retrospective, observational study on COVID-19 patients admitted to ordinary wards, to describe the clinical characteristics of patients at admission and bleeding and thrombotic events occurring during the hospital stay. Results  The number of hospitalized patients included in the START-COVID-19 Register was 1,135, and the number of hospitalized patients in ordinary wards included in the study was 1,091, with 653 (59.9%) being males and 71 years (interquartile range 59-82 years) being the median age. During the observation, two (0.2%) patients had acute coronary syndrome episodes and one patient (0.1%) had an ischemic stroke; no other arterial thrombotic events were recorded. Fifty-nine patients had symptomatic venous thromboembolism (VTE) (5.4%) events, 18 (30.5%) deep vein thrombosis (DVT), 39 (66.1%) pulmonary embolism (PE), and 2 (3.4%) DVT+PE. Among patients with DVT, eight (44.4%) were isolated distal DVT and two cases were jugular thrombosis. Among patients with PE, seven (17.9%) events were limited to subsegmental arteries. No fatal PE was recorded. Major bleeding events occurred in nine (1.2%) patients and clinically relevant nonmajor bleeding events in nine (1.2%) patients. All bleeding events occurred among patients receiving thromboprophylaxis, more frequently when treated with subtherapeutic or therapeutic dosages. Conclusion  Our findings confirm that patients admitted to ordinary wards for COVID-19 infection are at high risk for thromboembolic events. VTE recorded among these patients is mainly isolated PE, suggesting a peculiar characteristic of VTE in these patients.

Background  There is scarce information regarding the prevalence and clinical impact of saddle pulmonary embolism (PE) in patients with cancer. Objectives  This study aimed to assess the prevalence, clinical findings, and short-term outcomes of patients with cancer-related saddle PE including acute symptomatic and unsuspected events. Patients/Methods  Consecutive patients with cancer-related PE (March 1, 2006-October 31, 2014) were retrospectively reviewed by a chest radiologist to assess PE burden and signs of right ventricular (RV) overload. The clinical outcomes within 30 days were evaluated according to saddle versus nonsaddle PE. Results  Thirty-six (12%) out of 289 patients with newly diagnosed cancer-related PE presented with saddle PE. Saddle PE was found in 21 cases (58%) with acute symptomatic PE and the remaining 15 cases (42%) were found as unsuspected findings. Patients with saddle PE had more frequently experienced a previous thrombotic event (31 vs. 13%; p =0.008), and it occurred more frequently as an acute symptomatic event (58 vs. 39%; p =0.025) compared with those with nonsaddle PE. Signs of RV overload including RV/left ventricle ratio ≥1 (22 vs. 4%; p <0.001) and interventricular septum displacement (53 vs. 20%; p <0.001) were also more common in patients with saddle PE compared with nonsaddle PE. Overall, PE-related mortality, venous thromboembolism recurrence, and major bleeding within 30 days were found to be similar according to saddle versus nonsaddle PE. Conclusion  Saddle PE is not uncommon in patients with cancer-related PE including in those with unsuspected PE. Similar 30-day outcomes were found according to saddle versus nonsaddle PE in our cohort.

Background  Aspirin may reduce the risk of cancer, particularly gastrointestinal cancer, and venous thromboembolism (VTE). VTE can be the first symptom of occult cancer, but whether it is also a marker of occult cancer in aspirin users remains unknown. Therefore, we investigated the risk of cancer subsequent to VTE among users of low-dose aspirin. Methods  We conducted a population-based cohort study using data from Danish health registries for the years 2001 to 2018. We identified all patients with a first-time diagnosis of VTE who also redeemed a prescription for low-dose aspirin (75-150mg) within 90 days prior to the first-time VTE. We categorized aspirin users by the number of prescriptions filled as new users (<5 prescriptions), short-term users (5-19 prescriptions), and long-term users (>19 prescriptions). We computed the absolute cancer risks and standardized incidence ratios (SIRs) for cancer using national cancer incidence rates. Results  We followed-up 11,759 users of low-dose aspirin with VTE. Long-term users comprised 50% of aspirin users. The 1-year absolute risk of cancer was 6.0% for new users and 6.7% for short-term and long-term users, with corresponding SIRs of 3.3 (95% confidence interval [CI]: 2.8-4.0), 3.2 (95% CI: 2.9-3.7), and 2.8 (95% CI: 2.6-3.2), respectively. After the first year of follow-up, the SIR decreased to 1.2 (95% CI: 1.1-1.4) for new users, 1.1 (95% CI: 1.1-1.3) for short-term users, and 1.1 (95% CI: 1.0-1.2) for long-term users. Conclusion  VTE may be a harbinger of cancer, even in users of low-dose aspirin, regardless of duration of use.

Introduction  Immune thrombocytopenia (ITP) during pregnancy has received little attention from researchers. Reliable information about the outcome of mothers and newborns is required to properly counsel women who are pregnant or planning to become pregnant. Our primary outcomes were the frequency and severity of maternal and neonatal bleeding events in the setting of ITP in pregnancy. Mode of delivery, neonatal thrombocytopenia, and maternal/infant mortality were secondary outcomes. Material and Methods  We comprehensively reviewed the prospective studies that enrolled ≥20 pregnant women with primary ITP. Two reviewers, blinded to each other, searched Medline and Embase up to February 2021. Meta-analyses of the maternal and newborn outcomes were performed. Weighted proportions were estimated by a random-effects model. Results  From an initial screening of 163 articles, 15 were included, encompassing 1,043 pregnancies. The weighted event rate for bleeding during pregnancy was 0.181 (95% confidence interval [CI], 0.048-0.494). Most of these were nonsevere cases. The weighted event rates were 0.053 (95% CI, 0.020-0.134) for severe postpartum hemorrhage, 0.014 (95% CI, 0.008-0.025) for intracerebral hemorrhage, and 0.122 (0.095-0.157) for severe thrombocytopenia events in neonates (platelet count <50,000/μL). There were no reliable predictors of severe neonatal thrombocytopenia. The incidence of neonatal mortality was 1.06%. There were no maternal deaths. Conclusion  Primary ITP in pregnant women is rarely associated with poor outcomes.