INTRODUCTION:Heatstroke progresses from acute thermal injury to multiorgan dysfunction syndrome and heatstroke-induced coagulopathy (HIC). Although consumptive thrombocytopenia is a known hallmark of HIC, whether surviving platelets develop intrinsic qualitative impairments remains unclear. Autophagy maintains platelet mitochondrial quality and energy homeostasis, thereby ensuring appropriate platelet responsiveness to activating stimuli. However, its specific role in heatstroke-induced platelet dysfunction remains unexplored. This study examined the hemodynamic, hemostatic, and molecular consequences of heatstroke, focusing on platelet autophagic flux. MATERIALS AND METHODS:Male Wistar rats were subjected to environmental heat stress (42 °C) until their core temperature reached 41.1 °C. Hemodynamic parameters and multiorgan injury markers were monitored during the experimental period. At 6 h after heat stress, coagulation profiles and platelet functional experiments were assessed using platelet-count-adjusted platelet-rich plasma to differentiate qualitative dysfunction from quantitative depletion. Various platelet autophagy markers were evaluated through Western blotting. RESULTS:Heatstroke induced acute hyperthermia and compensatory cardiovascular responses, followed by hypotension, tachycardia, multiorgan dysfunction, thrombocytopenia, and prolonged coagulation times. Platelet functions were impaired following heatstroke, as evidenced by reduced platelet aggregation, fibrinogen binding, CD62P (P-selectin) expression, adhesion, and spreading. Furthermore, heatstroke was associated with decreased levels of the autophagy-related proteins Atg7, Beclin1, and LC3B, as well as the mitophagy-associated protein PINK1, accompanied by increased levels of BCL2 and p62. CONCLUSIONS:Multiorgan metabolic catastrophe coincides with substantial count-independent qualitative platelet dysfunction associated with arrested autophagic flux and impaired mitophagy in heatstroke. These findings challenge reliance on platelet count alone for managing HIC and highlight the autophagic machinery as a potential therapeutic target.
BACKGROUND:The optimal timing of reperfusion therapy in acute pulmonary embolism (PE) remains uncertain, despite guideline recommendations supporting urgent intervention in high-risk and selected intermediate-high-risk presentations. OBJECTIVE:The OPTIRAPE registry (Optimal Timing for Reperfusion in Acute Pulmonary Embolism) aims to evaluate the association between reperfusion timing and in-hospital outcomes and to characterize real-world treatment patterns and system-related delays in patients undergoing systemic thrombolysis (ST) or catheter-directed therapies (CDTs). DESIGN AND INTERVENTIONS:OPTIRAPE (NCT07436702) is a prospective, multicentre, observational registry enrolling consecutive adults with acute high-risk or intermediate-high-risk PE undergoing ST or CDTs reperfusion therapy across seven Italian hospitals with 24/7 access to advanced imaging and reperfusion strategies. Treatment decisions are based on the 2019 European Society of Cardiology guidelines and local practice, without protocol-mandated interventions. STUDY OUTCOMES:The primary exposure is time-to-reperfusion, defined as the interval from diagnostic confirmation of high-risk PE, or, in intermediate-high-risk patients, from clinical deterioration to initiation of reperfusion therapy. The primary endpoint is in-hospital mortality. Secondary endpoints include major bleeding, early haemodynamic deterioration, need for mechanical circulatory or respiratory support, recurrent venous thromboembolism, intensive care unit admission, and length of hospital stay. IMPLICATION:OPTIRAPE will provide granular real-world data on reperfusion timing, treatment modality, and inter-hospital variability in severe PE management. It will quantify the relationship between treatment delays and in-hospital outcomes and explore potential time thresholds associated with improved survival, informing future guideline recommendations and supporting the implementation of standardized, time-sensitive reperfusion pathways in acute PE.
BACKGROUND:Hemostatic drugs are frequently prescribed after colorectal cancer (CRC) surgery to prevent bleeding. However, in real-world practice, their net clinical benefit and thrombotic safety remain uncertain. This study aimed to evaluate the effectiveness and safety of prophylactic postoperative hemostatic drug use after CRC surgery. METHODS:This retrospective analysis was based on a prospectively collected multicenter CRC-venous thromboembolism (VTE) database involving 46 tertiary centers across 17 provinces in China between May 2021 and May 2022. Adults who underwent elective curative CRC surgery were included and followed up for 28 days. Exposure was defined as initiation of any prophylactic postoperative hemostatic drug (tranexamic acid, hemocoagulase, or carbazochrome sodium sulfonate) within 0-48 h after surgery in the absence of active bleeding at the first administration. Primary outcome was postoperative bleeding within 28 days; a surrogate outcome was hemoglobin decrease (dHb) ≥20 g/L. The secondary outcome was imaging-confirmed VTE, defined as postoperative DVT and/or PE; DVT was systematically screened within prespecified follow-up windows, whereas PE was assessed when clinically suspected. Inverse probability of treatment weighting (IPTW) based on propensity scores was used to balance baseline covariates, followed by weighted logistic regression. RESULTS:Among 1810 patients, 322 (17.8%) received prophylactic postoperative hemostatic drugs. After IPTW, all covariates achieved adequate balance, with standardized mean differences <0.10. Hemostatic drug use was not associated with reduced postoperative bleeding (2.9% vs. 1.7%; weighted odds ratio [OR]: 1.72, 95% confidence interval [CI]: 0.77-3.86) or dHb ≥20 g/L (21.4% vs. 26.1%; weighted OR: 0.77, 95% CI: 0.55-1.06). In contrast, hemostatic drug use was associated with a higher postoperative VTE rate (13.8% vs. 9.5%; weighted OR: 1.51, 95% CI: 1.02-2.24), mainly driven by DVT without PE, whereas PE events were rare and did not differ significantly between groups. Additional analyses showed that this association was also observed for symptomatic VTE (4.7% vs. 2.3%; weighted OR: 2.12, 95% CI: 1.03-4.37), whereas the association for asymptomatic/screening-detected VTE was not statistically significant after IPTW. Most VTE events with a DVT component involved distal DVT. Sensitivity analyses using winsorized weights yielded consistent estimates, and Propensity score trimming excluded no participants, supporting adequate overlap. In multivariable analysis, tumor-node-metastasis stage III-IV (OR: 3.20, 95% CI: 1.31-7.79) and intraoperative blood loss ≥50 mL (OR: 3.15, 95% CI: 1.20-8.22) were independent predictors of postoperative bleeding. CONCLUSIONS:In this retrospective analysis of a prospectively collected multicenter database, routine prophylactic postoperative hemostatic drug use after CRC surgery was not associated with a lower bleeding risk, but was associated with a higher postoperative VTE rate. Given the limited number of symptomatic events, the predominance of distal DVT, and the potential for residual confounding, this finding should be interpreted as a hypothesis-generating thrombotic safety signal rather than definitive causal evidence. Prophylactic hemostatic drugs should be used individually, with careful consideration of thrombotic risk.
Polyendocrine metabolic ovarian syndrome (PMOS), previously known as polycystic ovary syndrome (PCOS), is a complex disorder affecting females of reproductive age. Patients with PMOS can develop several comorbidities, including obesity, hyperlipidemia, arterial hypertension, insulin resistance, infertility, and increased risk for endometrial carcinoma. Venous thromboembolism (VTE) is another complication associated with PMOS, thought in part to be related to chronic inflammation leading to prothrombotic hemostatic changes. Hormonal therapy is the mainstay of management, but the presence of other comorbidities and risk factors such as thrombophilia and/or family history of VTE influences the choice of hormonal therapy. Management of this disorder requires multidisciplinary care of its gynecologic, cardiovascular, endocrine, and hemostatic components. In this review, a summary of the diagnosis and management of PMOS is provided with an emphasis on hemostatic considerations. We highlight 1) the diagnostic criteria and general management of PMOS, 2) Hormonal therapy and VTE risk considerations in PMOS management, and 3) Infertility management and the potential risk for thrombosis in patients with PMOS.
Background Bleeding in early pregnancy is reported in 1 in 4 of pregnancies and is linked to increased risks of miscarriage, preterm birth, low birth weight, placental abruption, and stillbirth. Current treatments are limited and none of the recommended treatments target cessation of bleeding. Tranexamic acid (TXA), an antifibrinolytic agent, presents a potential option for halting bleeding in early pregnancy, potentially reducing the risk of associated adverse outcomes. Aims To review the current literature on the use and efficacy of TXA in early pregnancy. Methods A scoping review was conducted using JBI methodology. Searches were performed in Embase, Medline, CENTRAL, and grey literature. Three separate searches assessed TXA's efficacy in early pregnancy, safety profile during pregnancy, and potential teratogenicity. Results Four studies met inclusion criteria for efficacy: three non-randomised prospective trials and one observational study, totaling 319 patients. Studies had small sample sizes and varied methodologies. For safety, 30 studies involving 76,302 patients were included: 13 systematic reviews/meta-analyses, 13 RCTs, 2 retrospective cohorts, 1 prospective case-control study, and 1 open-label dose-ranging study. Most focused on postpartum haemorrhage. No significant increase in venous thromboembolism was observed with TXA versus control. No case-control studies evaluated teratogenicity directly. However, 22 studies from 14 countries reported TXA use in pregnancy (not related to postpartum haemorrhage). Among 234 pregnancies exposed to TXA, 230 (98%) resulted in live births. Conclusion Evidence for TXA use in early pregnancy is limited, with small, low-quality studies. Larger, high-quality trials are needed to determine safety and efficacy.
Objective To clarify how centrifugal blood pump-induced non-physiological shear stress affects platelet adhesion and aggregation, explaining the coexistence of thrombosis and bleeding during centrifugal pump support. Methods Blood samples collected before and after centrifugal pump operation were used. Platelet adhesion, aggregation, and binding forces were evaluated using collagen and fibrinogen coated microfluidic chips and micropost arrays. Platelet receptor expression, vWF function, and pro-aggregatory factors were further investigated. Results After centrifugal pump operation, platelet adhesion to collagen decreased, especially under higher perfusion shear rates. The platelet and collagen binding force decreased from 33.04 nN to 8.73 nN, indicating impaired adhesive stability. This was associated with reduced platelet GPVI and GPIbα receptor expression, decreased vWF activity, and weakened platelet-vWF binding, suggesting inhibition of both GPVI mediated and vWF/GPIbα mediated adhesion. In contrast, platelet binding to fibrinogen increased, especially under higher perfusion shear rates. The platelet and fibrinogen binding force increased from 12.85 nN to 42.29 nN, indicating enhanced aggregation stability. This was accompanied by increased platelet GPIIb/IIIa receptor activation and elevated pro-aggregatory factors. However, prolonged centrifugal pump operation reduced platelet responsiveness to secondary stimulation and decreased GPIIb/GPIIIa subunit availability, suggesting that sustained shear exposure limits further platelet activation and aggregation. Conclusion Centrifugal blood pump induced non-physiological shear stress impairs collagen mediated initial adhesion while enhancing fibrinogen mediated aggregation. Sustained shear exposure weakens platelet secondary responsiveness and limits further enhancement of aggregation hemostasis. These findings reveal a potential mechanism for the coexistence of thrombosis and bleeding and provide a microfluidic method for hemocompatibility assessment.
BACKGROUND:Unprovoked venous thromboembolism (VTE) is a marker of occult malignancy. While this association is well established for deep vein thrombosis (DVT) and pulmonary embolism (PE), evidence for cerebral venous thrombosis (CVT) remains limited. We evaluated the incidence and risk of newly diagnosed cancer following DVT/PE and CVT. METHODS:Using administrative healthcare databases from the Lombardy region (2002-2023), we included subjects aged ≥30 years hospitalised for incident DVT/PE or CVT and age- and sex-matched controls. Cancer incidence was assessed by cumulative incidence functions (CIFs) and standardized incidence ratios (SIRs), with subdistribution hazard ratios (sHRs). RESULTS:109,371 DVT/PE (mean age 73 years; 57% female) and 1929 CVT patients (mean age 53 years; 68% female) were included. During follow-up, cancer was diagnosed in 10% and 4% of DVT/PE and CVT patients, respectively, corresponding to a higher cancer risk in DVT/PE (sHR 1.73 95% CI, 1.68-1.79) and CVT patients (sHR 1.42 95% CI 1.08-1.89) in comparison with matched controls. Incidence differences narrowed over time; SIRs of 3.85 [95% CI 2.11-7.26] and 4.61 [95% CI 4.37-4.87] at 1 year, and 1.47 [95% CI 1.10-1.95] and 2.12 [95% CI 2.06-2.19] at 5 years, in CVT and DVT/PE, respectively. In comparison with control group, the incidence of cancer was always higher in the DVT/PE group while for CVT patients for hematologic and central nervous system (CNS) cancers. CONCLUSIONS:Similar to unprovoked VTE, CVT should be considered a marker of occult cancer, particularly hematologic and CNS malignancies, with the highest vigilance warranted during the first year.
Background Venous thromboembolism (VTE), which includes deep vein thrombosis (DVT) and pulmonary embolism (PE), is one of the major causes of mortality in pregnant women. Clinical practices followed by obstetricians in different hospitals might influence the incidence and prevalence rates of VTE. This obstetrician-based survey was conducted to understand the establishment of VTE prevention and treatment system and its current scenario in various hospitals for preventing VTE during pregnancy. Objectives An obstetrician-based survey was conducted to understand the establishment of VTE prevention and treatment system during pregnancy and its current scenario in various hospitals across China. Methods A questionnaire-based survey was conducted among 1128 obstetricians from July 1 to 312,024 in 22 provinces, 5 autonomous regions and 4 municipalities across China. Responses on hospital infrastructure (grade, type, resource allocation) with respect to VTE management, VTE prevention and treatment system establishment, and health education was collected. The data was analyzed by using R software and P value of <0.05 was considered significant. Results Ultrasonography of the lower extremity veins was not performed in 11.89% of the hospitals, while the unavailability of computed tomographic pulmonary angiography (CTPA) and pulmonary ventilation/perfusion (V/Q) scintigraphy was reported in over 50% and 80% of the hospitals, respectively. Tertiary hospitals outperformed primary and secondary hospitals in all VTE prevention system indicators (P < 0.001), and general hospitals surpassed specialized hospitals in multiple aspects (P < 0.05). Only 67.1% of physicians performed VTE risk assessment on all pregnant women, with significant disparities by hospital level (P < 0.001). VTE patient education was not universal and varied significantly by hospital level (P < 0.001), being most comprehensive in tertiary hospitals. Conclusion VTE prevention and treatment infrastructure in some Chinese hospitals are insufficient. The survey identified gaps between the clinical practice of obstetricians and national/international guidelines or consensus requirements. Following uniform clinical practices across the different hospital settings would help to improve VTE prevention in pregnant women in China.
BACKGROUND:The burden of subclinical atherosclerosis in patients with retinal vein occlusion (RVO) remains incompletely understood. METHODS:Cross-sectional study of consecutive adult patients with RVO underwent cardiovascular risk assessment using SCORE2/SCORE2-OP and bilateral carotid ultrasonography. Patients were stratified into three groups: antiphospholipid syndrome (APS), conventional cardiovascular risk factors (CRF+), and those without (CRF-). Carotid plaque was defined according to Mannheim consensus criteria. Receiver operating characteristic (ROC) analysis evaluated the discriminative performance of SCORE2 in plaque detection. RESULTS:A total of 500 patients were included (55 APS; 413 CRF+ and 32 CRF-). Carotid plaque prevalence increased progressively across SCORE2 categories (27.1% in low-moderate, 55.6% in high, and 75.3% in very high risk; p < 0.001). APS patients demonstrated a plaque burden comparable to CRF+ individuals, with 55-75% plaque prevalence in high/very high-risk strata. Notably, plaque was detected in a subset of patients classified as low-moderate risk, particularly within the APS group. SCORE2/SCORE2-OP showed a moderate discrimination for plaque detection (AUC 0.76; 95% CI 0.72-0.80). CONCLUSIONS:RVO is associated with a substantial burden of subclinical atherosclerosis measured by carotid ultrasonography. APS confers an accelerated atherosclerotic phenotype comparable to conventional cardiovascular risk. SCORE2/SCORE2-OP tools alone may underestimate vascular burden in this population.
BACKGROUND:Hereditary factor XII (FXII) deficiency is a rare autosomal recessive disorder rarely causing spontaneous bleeding, though its link to thrombosis remains debated. This study characterized clinical and genetic features of FXII deficiency in Chinese Han patients and performed preliminary in vitro functional assays. METHODS:Clinical and coagulation data from 14 patients diagnosed 2018-2025 were retrospectively collected. Whole-exome sequencing identified F12 variants, followed by ACMG-based pathogenicity assessment. In vitro secretion and chromogenic activity assays were conducted on five novel mutants. Untargeted metabolomics was performed on 10 case-control pairs for hypothesis generation. Semi-quantitative plasma FXII antigen ELISA was completed for eight patients. RESULTS:All patients exhibited prolonged APTT (mean 155.9 ± 89.7 s) and severely reduced FXII activity (mean 3.8 ± 4.0%). Fifteen distinct F12 variants were identified, including eight novel ones. The frameshift variant c.1092dup was homozygous in 28.6% of this single-center cohort. In vitro, p.Q254P, p.S528Y, p.G376W, and p.V211Wfs*40 showed severely impaired secretion, whereas p.A255S secreted normally. In a silica-induced chromogenic assay using crude cell supernatants, p.A255S retained approximately 95% of wild-type activity; however, functional consequences remain incompletely characterized. Untargeted metabolomics revealed differential metabolites enriched in lipid and amino acid pathways. ELISA showed reduced plasma FXII antigen (23.9%-30.5% of normal), though these data are semi-quantitative due to dilution requirements and differences in sample storage duration. CONCLUSION:This study delineates clinical and genetic profiles of Chinese Han FXII-deficient patients, expands the F12 variant spectrum with eight novel mutations, and provides preliminary in vitro secretory evidence. The high c.1092dup homozygous rate requires validation in larger multi-center cohorts. All findings are constrained by the small single-center design.
Cofactor-independent activity of FIX has previously been achieved in FIX-IDAV and FIX-FIAV variants containing L6F, V181I, E185D, K265A, and I383V substitutions. Cofactor-dependent FIX hyperactivity was attained through the V10K, R338L, and S377W (KLW) modifications. We evaluated whether combining IDAV/FIAV and KLW substitutions could enhance cofactor-independent activity and elucidated the biochemical mechanisms underlying FVIII-independent FIX-FIAV function. Recombinant FIX variants, expressed in HEK293 cells, were analyzed for FIX-specific and FVIII-equivalent clotting activities. Highly purified FIX-FIAV was characterized using purified component assays and FXIa-triggered thrombin generation in FVIII-deficient plasma. FIX-IDAV-KLW and FIX-FIAV-KLW exhibited 20-28-fold higher FIX-specific activity and a modest twofold increase in FVIII-equivalent clotting activity. Owing to thrombotic safety concerns, KLW combinations were not further pursued. FIX-FIAV displayed normal FIX-specific activity and fourfold enhanced FVIII-equivalent clotting activity. The FIAV substitutions did not alter activation by the extrinsic (TF-FVIIa) or intrinsic (FXIa) pathways, nor cofactor-dependent FX activation, but conferred FVIII-independent FX conversion. Kinetic analyses revealed a modified active site conformation with a trend toward reduced antithrombin inhibition. In FVIII-deficient plasma, FIX-FIAV dose-dependently increased FXIa-triggered thrombin generation by shortening the lag time and time to peak and shifted coagulation phenotype categories based on FVIII-equivalent thrombin generation (TG) activity from severe toward moderate/mild ranges in plasma-based models, without exceeding normal FVIII-equivalent TG activity. FIX-FIAV represents a FIX variant with FVIII-independent activity, normal FIX-specific activity, and reduced inactivation by antithrombin. Targeted modification of regions surrounding the FIXa active site enables allosteric activation, providing a potential foundation for novel bypassing strategies in hemophilia A therapy.
OBJECTIVES:To define distinct coagulation-fibrinolysis phenotypes in traumatic hemorrhagic shock (THS) compared with upper gastrointestinal bleeding-associated hemorrhagic shock (UGIB-HS), and to explore whether the tissue plasminogen activator/plasminogen activator inhibitor-1 complex (tPA/PAI-1 complex) provides insight into etiology-specific fibrinolytic regulation and early bleeding-related risk in THS. METHODS:This retrospective observational study included 216 patients with blunt THS, 30 patients with UGIB-HS, and 30 blunt trauma controls without shock. Admission levels of tPA/PAI-1 complex, thrombin-antithrombin complex (TAT), plasmin-α2-antiplasmin complex (PIC), fibrinogen, lactate, Injury Severity Score (ISS), and Sequential Organ Failure Assessment (SOFA) score were analyzed. Multivariable logistic regression and receiver operating characteristic (ROC) analyses were performed. RESULTS:Compared with UGIB-HS, THS showed markedly higher TAT and PIC levels (>9-fold and >8-fold, respectively), lower fibrinogen levels, and lower tPA/PAI-1 complex concentrations (14.43 ± 3.79 vs. 15.16 ± 3.25 ng/mL, P = 0.003). Compared with trauma controls, THS patients exhibited increased tPA/PAI-1 complex, TAT, and PIC levels (all P < 0.0001). In THS, tPA/PAI-1 complex correlated positively with TAT, PIC, ISS, and SOFA score, and negatively with fibrinogen (all P < 0.001). After adjustment for age, lactate, ISS, and fibrinogen, tPA/PAI-1 complex remained independently associated with bleeding-related adverse outcomes (OR 1.368, 95% CI 1.216-1.561), with a multivariable model AUC of 0.878 (95% CI 0.834-0.923). CONCLUSIONS:THS exhibits a distinct coagulation-fibrinolysis phenotype characterized by concurrent activation of thrombin and plasmin generation compared with UGIB-HS. The altered tPA/PAI-1 complex profile may reflect etiology-specific regulation of balance between fibrinolytic activation and endogenous regulatory responses and provides complementary prognostic information for early risk stratification in THS.
