Coagulation Research Articles

Prophylactic Treatment of Children with Hemophilia in Sweden.

Hemophilia A/B are caused by deficiency or lack of coagulation factors VIII (FVIII) or factor IX (FIX), respectively, in plasma. A person with hemophilia develops bleeding in the joints and muscles at an early age, which, if left untreated, leads to early arthropathy. Preventive treatment can be achieved by regular (prophylactic) administration of FVIII/FIX. In 1958, this was implemented on a small scale in Sweden with FVIII in patients with severe hemophilia A, and in those with hemophilia B in 1972 when FIX became available. However, there were problems with human immunodeficiency virus and hepatitis infection from contaminated blood products. In the 1990s, recombinant FVIII and FIX concentrates were introduced. The major remaining problems then were the development of inhibitors, and the need for a venous route for the injections in very young children. High-titer inhibitors were treated by immune tolerance induction according to a modified model of the original Bonn high-dose protocol. A central venous line, i.e., Port-A-Cath, has enabled early prophylaxis in many children with poor venous access and has enabled the early start of home treatment with adequate injection frequency. Scoring systems for X-rays, magnetic resonance imaging, and function of joints were developed early in Sweden and have been widely disseminated worldwide, partly with modifications. Extended half-life products with half-life increased three to five times have been developed, which can provide superior bleed protection when dosed once-weekly and can maintain therapeutic trough levels when administered less frequently. The ultimate prophylaxis therapy in the future may be gene therapy.

Rare bleeding disorders: Advances in management

Inherited factor coagulation deficiencies and vascular bleeding disorders, associated with bleeding of various severity, are often classified as rare bleeding disorders (RBDs). These include inherited fibrinogen disorders, inherited platelet function disorders (IPFD) and hereditary haemorrhagic telangiectasia (HHT). In the last decades, there have been large increases in knowledge on the epidemiology, genetics, physiopathology, clinical features, and diagnosis of RBDs, but improvements in management have been more limited and remain challenging. The treatment mainstay of RBDs is based only on replacement of a few available coagulation factor concentrates or cryoprecipitates. There is growing interest in therapeutic agents that enhance coagulation or inhibiting anticoagulant pathways in RBDs. In severe IPFD, the optimal platelet transfusion strategy is not yet established. Moreover, data is scarce on the effectiveness and safety of desmopressin and/or antifibrinolytic drugs often used for milder IPFD treatment. The best fibrinogen replacement strategy (prophylaxis vs. on demand) in afibrinogenemia is still debated. Similarly, the optimal trough fibrinogen target level for treatment of acute bleeding, and the role of fibrinogen replacement during pregnancy in mild hypofibrinogenemia and dysfibrinogenemia, have not been properly evaluated. The therapeutic arsenal in HHT includes antifibrinolytics and a series of antiangiogenic agents whose potential efficacy has been tested in small studies or are under investigation for treatment of bleeding. However, there is need to address several issues, including the optimal dosing strategies, the potential emergent toxicity of longer-term use, and the impact of systemic antiangiogenic treatment on visceral arteriovenous malformations.

Plant mucus-derived microgels: Blood-triggered gelation and strong hemostatic adhesion

Arrest of bleeding usually applies clotting agents to trigger coagulation procedures or adhesives to interrupt blood flow through sealing the vessel; however, the efficiency is compromised. Here, we propose a concept of integration of hemostasis and adhesion via yam mucus's microgels. The mucus microgels exhibit attractive attributes of hydrogel with uniform size and shape. Their shear-thinning, self-healing and strong adhesion make them feasible as injectable bioadhesion. Exceptionally, the blood can trigger the microgels' gelation with the outcome of super extensibility, which leads to the microgels a strong hemostatic agent. We also found a tight gel adhesive layer formed upon microgels' contacting the blood on the tissue, where there is the coagulation factor XIII triggered to form a dense three-dimensional fibrin meshwork. The generated structures show that the microgels look like hard balls in the dispersed phase into the blood-produced fibrin mesh of a soft net phase. Both phases work together for a super-extension gel. We demonstrated the microgels' fast adhesion and hemostasis in the livers and hearts of rabbits and mini pigs. The microgels also promoted wound healing with good biocompatibility and biodegradability.

Prevalence and Characteristics of Plasmid-Encoded Serine Protease EspP in Clinical Shiga Toxin-Producing Escherichia coli Strains from Patients in Sweden.

Shiga toxin-producing Escherichia coli (STEC) infection can cause a broad spectrum of symptoms spanning from asymptomatic shedding to mild and bloody diarrhea (BD) and even life-threatening hemolytic-uremic syndrome (HUS). As a member of the serine protease autotransporters of Enterobacteriaceae (SPATE) family, EspP has the ability to degrade human coagulation factor V, leading to mucosal bleeding, and also plays a role in bacteria adhesion to the surface of host cells. Here, we investigated the prevalence and genetic diversity of espP among clinical STEC isolates from patients with mild diarrhea, BD, and HUS, as well as from asymptomatic individuals, and assessed the presence of espP and its subtypes in correlation to disease severity. We found that 130 out of 239 (54.4%) clinical STEC strains were espP positive, and the presence of espP was significantly associated with BD, HUS, and O157:H7 serotype. Eighteen unique espP genotypes (GTs) were identified and categorized into four espP subtypes, i.e., espPα (119, 91.5%), espPγ (5, 3.8%), espPδ (4, 3.1%), and espPε (2, 1.5%). espPα was widely distributed, especially in strains from patients with BD and HUS, and correlated with serotype O157:H7. Serogroup O26, O145, O121, and O103 strains carried espPα only. Ten GTs were identified in espPα, and espPα/GT2 was significantly associated with severe disease, i.e., BD and HUS. Additionally, espP was strongly linked to the presence of eae gene, and the coexistence of espPα and stx2/stx2a + stx2c was closely related to HUS status. To sum up, our data demonstrated a high prevalence and genetic diversity of the espP gene in clinical STEC strains in Sweden and revealed an association between the presence of espP, espP subtypes, and disease severity. espP, particularly the espPα subtype, was prone to be present in more virulent STEC strains, e.g., "top-six" serotypes strains.

Relationship Between the Incidence of Pulmonary Embolism and the Quantitative Level of Air Pollution (NO2, SO2, CO, O3, and PM10) in Patients Referred to Mashhad Hospitals in 2019

Background: Air pollution is known to be associated with increased levels of inflammatory markers, vascular endothelial damage, and alterations in blood coagulation factors. It represents one of the most significant environmental hazards in urban areas, with adverse effects on the health of the population. Objectives: This study aimed to investigate the relationship between the incidence of pulmonary embolism (PE) and the quantitative levels of various air pollution parameters. Methods: In this descriptive-analytical (cross-sectional) study, we examined all patients diagnosed with PE who were referred to Ghaem and Imam Reza (AS) Hospitals in Mashhad during the year 2019. Daily data on each air pollutant, including NO2, SO2, CO, O3, and PM10, were obtained from the Meteorological Center. For each patient's assessment, we considered the average pollution levels over the past 30 days. The collected data were subsequently analyzed using independent samples t-tests and the Mann-Whitney U test in SPSS 22. Results: The findings of this study revealed a statistically significant association between elevated levels of PM10 and O3 and the occurrence of PE. However, no such relationship was observed for NO2 and CO in relation to the risk of PE. Conclusions: It can be concluded that increased levels of PM10 and O3 are linked to a higher risk of developing PE, while other pollutants showed no evidence of association in this study.

Direct thrombin inhibiting coating for active coagulant management in extracorporeal circulation

Existing anticoagulant coatings are designed to inhibit the initial attachment of coagulant factors, but they frequently suffer from undesirable coating defects that result in a declined physical barrier function. Heparin, serving as a commercialized pharmacological coating via the activation of antithrombin, frequently causes heparin-induced thrombocytopenia. Here, we developed an argatroban-polyphenol conjugate proteinaceous coating (named PDA-BSA-AG coating) that actively inhibits thrombin, in contrast to previously reported passive coatings and indirect pharmacological anticoagulants. Following clinical treatment standards, a magnetic levitation ventricular assist system was employed for the first time to accomplish extracorporeal circulation utilizing PDA-BSA-AG coated tubes. The results show that the clotting time of the PDA-BSA-AG coating was 68.9 % longer than that of clinical Bioline heparin coating. It is noteworthy that argatroban not only delivers anticoagulant effectiveness but also enhances patient safety and reduces the occurrence of complications. A novel combination of the primary specific proteins of platelets and the coagulation-inflammatory cascade reaction of the cytokines and complement systems explained the anticoagulation mechanism. Reliable biocompatibility (hemolysis, cytotoxicity, and antibacterial activity) was noted, along with impressive coating stability for up to 6 h of extracorporeal circulation. These results above suggested that the PDA-BSA-AG coating is promising for a wide range of blood-contacting devices.

Molecular mechanism analysis of a family with hereditary coagulation F Ⅺ deficiency caused by compound heterozygous mutations

A 34 year old female patient was scheduled to undergo surgical resection due to a "breast nodule". Preoperative examination revealed an activated partial thromboplastin time (APTT) of 66.2 seconds, coagulation factor Ⅺ activity (FⅪ: C) of 2%, and FⅪ antigen (FⅪ: Ag) of 40.3%. The patient and family members showed no abnormal bleeding symptoms. Diagnosed as hereditary coagulation factor Ⅺ deficiency. Genetic testing revealed that the F11 gene had a heterozygous nonsense mutation in exon 10, c.1107C>A (p.Tyr351stop), and a heterozygous missense mutation in exon 13, c.1562A>G (p.Tyr503Cys). The father and son were p Heterozygous carriers of Tyr351stop mutation, while the mother and daughter are p Heterozygous carriers of Tyr503Cys mutations. The in vitro expression results showed that p The Tyr351stop mutation resulted in a significant decrease in the transcription level of F11 gene, while p The Tyr503Cys mutation has no effect on the transcription level and protein expression level of F11 gene, but it leads to a significant decrease in the level of FⅪ:C in the cell culture supernatant.

Potential Mechanism of Platelet GPIIb/IIIa and Fibrinogen on Retinal Vein Occlusion

Purpose To explore the role of coagulation and fibrinolytic factors, and the potential mechanism of platelet aggregation in the pathogenesis of retinal vein occlusion. Methods Coagulation and fibrinolytic parameters in patients with retinal vein occlusion were determined using hemagglutinin and HISCL-5000. Relationships between these elevated parameters and factors representing typical clinical manifestations of retinal vein occlusion were examined, and these parameters were analyzed using a STRING database to indicate the potential role of platelet aggregation. Platelet glycoprotein IIb/IIIa (GPIIb/IIIa) levels were evaluated by flow cytometry after antiplatelet treatment in patients and mouse models. Furthermore, the GPIIb/IIIa ligand fibrinogen in peripheral blood and retina of mouse models was assessed by the turbidimetric method and real-time PCR, respectively. Results In patients, significant increases in peripheral blood fibrinogen and GPIIb/IIIa levels were observed (p = 0.0040, p < 0.0001, respectively). A positive correlation was observed between macular thickness (MT) and both fibrinogen and GPIIb/IIIa (r = 0.4528, p = 0.0063; r = 0.3789, p = 0.0427, respectively). After intravitreal injections of anti-vascular endothelial growth factor drugs, a significant reduction in fibrinogen levels was observed (p = 0.0072). In addition, the use of antiplatelet drugs resulted in a significant decrease in GPIIb/IIIa (p < 0.0001). In a mouse model, antiplatelet therapy significantly reduced both peripheral blood and retina fibrinogen levels and the overall rate of vein occlusion 3 days after occlusion (p < 0.0005). In addition, the reduction in GPIIb/IIIa levels after antiplatelet therapy was remarkable. Conclusion Fibrinogen and GPIIb/IIIa may be involved in retinal vein occlusion and blocking platelet aggregation may be a new therapeutic approach for retinal vein occlusion.

Risk factors, prevention, and therapy of intraluminal stent thrombosis in frozen elephant trunk prostheses-what we know so far.

Intraluminal thrombus formation (ILT) is a recently discovered and highly clinically relevant complication after frozen elephant trunk implantation in cardiovascular surgery. In this phenomenon, a thrombus forms within the lumen of the stent graft component of the frozen elephant trunk prosthesis and puts the patient at risk for downstream embolization with visceral or lower limb ischemia. Incidence of ILT reported in the currently available studies ranges from 6% to 17% of patients after frozen elephant trunk implantation. Adverse thromboembolic events include acute occlusion of the celiac and superior mesenteric arteries, both renal arteries as well as acute lower limb ischemia due to iliac or femoral artery embolization that not infrequently require interventional or open embolectomy. Therefore, the presence of ILT is associated with increased short-term mortality and morbidity. Currently proposed strategies to avoid ILT formation include a more aggressive anticoagulation management, minimization of postoperative coagulation factor application, and even technical optimizations of the stent graft portion itself. If ILT is manifested, the therapeutic strategies tested to date are long-term escalation of anticoagulation and early endovascular extension of the FET stent graft with overstenting of the intraluminal thrombus. The long-term efficiency of these prophylactic and therapeutic measures has yet to be proven. Nonetheless, all surgeons performing the frozen elephant trunk procedure must be aware of the risk of ILT formation to facilitate a timely diagnosis and therapy.

Fitusiran prophylaxis in people with hemophilia A or B who switched from prior BPA/CFC prophylaxis: the ATLAS-PPX trial

AbstractFitusiran, a subcutaneous investigational small interfering RNA therapeutic, targets antithrombin to rebalance hemostasis in people with hemophilia A or B (PwHA/B), irrespective of inhibitor status. This phase 3, open-label study evaluated the efficacy and safety of fitusiran prophylaxis in males aged ≥12 years with hemophilia A or B, with or without inhibitors, who received prior bypassing agent (BPA)/clotting factor concentrate (CFC) prophylaxis. Participants continued their prior BPA/CFC prophylaxis for 6 months before switching to once-monthly 80 mg fitusiran prophylaxis for 7 months (onset and efficacy periods). Primary end point was annualized bleeding rate (ABR) in the BPA/CFC prophylaxis and fitusiran efficacy period. Secondary end points included spontaneous ABR (AsBR) and joint ABR (AjBR). Safety and tolerability were assessed. Of 80 enrolled participants, 65 (inhibitor, n = 19; noninhibitor, n = 46) were eligible for ABR analyses. Observed median ABRs were 6.5 (interquartile range [IQR], 2.2-19.6)/4.4 (IQR, 2.2-8.7) with BPA/CFC prophylaxis vs 0.0 (IQR, 0.0-0.0)/0.0 (IQR, 0.0-2.7) in the corresponding fitusiran efficacy period. Estimated mean ABRs were substantially reduced with fitusiran by 79.7% (P = .0021) and 46.4% (P = .0598) vs BPA/CFC prophylaxis, respectively. Forty-one participants (63.1%) experienced 0 treated bleeds with fitusiran vs 11 (16.9%) with BPAs/CFCs. Median AsBR and AjBR were both 2.2 with BPA/CFC prophylaxis and 0.0 in the fitusiran efficacy period. Two participants (3.0%) experienced suspected or confirmed thromboembolic events with fitusiran. Once-monthly fitusiran prophylaxis significantly reduced bleeding events vs BPA/CFC prophylaxis in PwHA/B, with or without inhibitors, and reported adverse events were generally consistent with previously identified risks of fitusiran. This trial was registered at www.ClinicalTrials.gov as #NCT03549871.

Diagnosis and treatment challenges in lower resource countries: State-of-the-art.

The 2022 World Federation of Haemophilia Annual Global Survey (AGS) reports that 454,690 patients with inherited bleeding disorders (IBD) have been identified globally. While this represents noteworthy progress, haemophilia epidemiology data indicate that 75% of people with inherited bleeding disorders living in low-income and low-to-middle-income countries have yet to be diagnosed. The AGS also revealed that 11 billion clotting factor units are available to treat haemophilia A and B globally. Due to a lack of finance, these treatments are unavailable to haemophilia in low-income countries with a consequence lack of access equity for haemophilia treatment in these communities. This sobering reality is not limited to haemophilia but applies to von Willebrand Disease (VWD). While VWD is the most prevalent IBD, only 103,844 people living with this condition have been diagnosed globally. Of the diagnosed patients, only a fraction live in low- or middle-income countries. Moreover, the majority of VWD patients are still treated sub-optimally without replacement therapies or prophylaxis, both of which are now accepted as global standards of care. In this state-of-the-art review, the authors reflect on three issues. First, the minimum elements required to diagnose haemophilia in a resource-constrained setting are identified. Second, this review points to the critical stakeholders and outlines their roles in removing access to haemophilia treatment barriers. Finally, the authors examine von Willebrand disease's ongoing diagnostic and treatment challenges and compare these to haemophilia. With the rapidly evolving novel therapies, the therapeutic landscape of all IBD will likely change for the better.

LIVER ENZYME ALTERATIONS AFTER LAPAROSCOPIC CHOLECYSTECTOMY IN A TERTIARY CARE CENTER

Objective: Cholelithiasis is a prevalent global health concern, with laparoscopic cholecystectomy (LC) emerging as the preferred surgical intervention. While LC offers an advantage such as shorter hospital stays, it poses potential risks, including cardiovascular impediments because of hemodynamic and ventilatory changes. The current research study was done to assess the impact of LC on hematological parameters, comparing pre-operative and post-operative levels. Methods: The study comprised 51 subjects undertaking LC, and preoperative and postoperative blood samples were analyzed for various hematological parameters. Parameters investigated included hemoglobin (Hb), mean corpuscular volume, mean corpuscular Hb, mean corpuscular Hb concentration, hematocrit, platelet count, mean platelet volume (MPV), and liver function tests such as alanine transaminase and alkaline phosphatase. Results: Preliminary findings demonstrated significant alterations in hematological parameters post-LC. Changes in MPV, leukocytes, neutrophils, neutrophil–lymphocyte ratio, platelet–lymphocyte ratio, and coagulation factors were observed. Moreover, there was a notable proliferation in thromboembolic measures connected with pneumoperitoneum pressure and surgery duration. Conclusion: LC induces substantial changes in hematological parameters, potentially contributing to postoperative complications. Understanding these alterations is crucial for implementing appropriate pre-, peri-, and post-operative measures to minimize morbidity, mortality, and overall health-care costs. Further investigations are required in interpreting the principal mechanisms and refine strategies for optimizing patient outcomes in LC.

The role of coagulation factors VIII, IX and XI in the prediction and mediation of recurrent thrombotic events in children with non-central venous catheter deep vein thrombosis

BackgroundThe role of elevated coagulation factors VIII (FVIII), FIX, FXI for the prediction of recurrent thrombotic events in children after an index non-central venous catheter (non-CVC) related deep vein thrombosis (DVT) remains unclear. ObjectiveThis study investigates the predictive role of FVIII, FIX, and FXI for recurrent thrombosis in children with index non-CVC DVTs, and the mediation effect of FVIII on chronic inflammation and recurrent thrombosis. MethodsChildren aged 0–18 years diagnosed with an index non-CVC related DVT (1993–2020) were included in this single-center retrospective cohort study. Plasma levels of FVIII, FIX, FXI were measured cross-sectionally ≥30 days after the acute DVT. The association between the continuous variables FVIII, FIX, FXI and thrombosis recurrence was investigated using uni- and multivariable logistic regression, adjusting for age, sex, and chronic inflammation. Mediation analysis assessed the role of FVIII as a mediator between chronic inflammation and recurrent thrombosis. Ethics approval was obtained. ResultsA total of 139 children with an index non-CVC related DVT were included. Thirty-eight (27 %) had a recurrent thrombosis at a median of 237 days (P25-P75 65-657 days) after the index DVT. In uni- and multivariable-analysis, FVIII, FIX or FXI did not predict thrombosis recurrence; However, chronic inflammation was an independent predictor. There was no evidence that FVIII mediated the effect of chronic inflammation on thrombosis recurrence. ConclusionWe found no evidence that elevated FVIII, FIX or FXI predicted thrombosis recurrence, or evidence of a mediating role of FVIII. Underlying chronic inflammation predicted venous recurrent thrombotic events in this cohort.

How to investigate mild to moderate bleeding disorders and bleeding disorder of unknown cause.

A bleeding tendency is one of the most common complaints observed by hematologists. It is challenging to differentiate a clinically insignificant bleeding from a bleeding phenotype that requires hemostatic evaluation and medical intervention. A thorough review of personal and familial history, objective assessment of bleeding severity using a bleeding assessment tool, and a focused physical examination are critical to correctly identifying suspected patients with mild to moderate bleeding disorders (MBDs). A basic laboratory work-up should be performed in all patients referred for a bleeding tendency. If a hemostatic abnormality is found such as evidence of von Willebrand disease, a platelet function disorder, or a coagulation factor deficiency, more extensive testing should be performed to further characterize the bleeding disorder. Conversely, if all results are normal the patient is considered to have bleeding disorder of unknown cause (BDUC). For patients with BDUC, further evaluation may include non-routine testing to look for rare bleeding disorders not detected by routine hemostasis tests, such as thrombomodulin-associated coagulopathy, tissue factor pathway inhibitor-related bleeding disorder, hyperfibrinolytic-bleeding disorders or impaired tissue factor production. In this review, we summarize the stepwise diagnostic procedure in MBDs and provide some insights into the biological features of BDUC.

Modern Treatment of Valvulopathies in Patients with Congenital Hemophilia.

Hemophiliacs can develop cardiovascular diseases, including valvulopathies of various etiologies and severities. Some require surgical treatment. Performing cardiac surgery in hemophiliacs is a challenge because they maintain an increased risk of bleeding throughout their lives. Our review shows that with a multidisciplinary team and careful planning, cardiac surgery can be safely performed in these patients. Valve repair and bioprosthetic valves should be preferred over mechanical valves to avoid life-long anticoagulation. In patients who cannot receive a bioprosthetic valve, the use of the On-X mechanical valve might be considered because it requires less intensive anticoagulation after 3 months of treatment. Antithrombotic treatment is feasible in hemophiliacs only if the coagulation factor level is kept constantly above a specific trough limit. Our review is valuable because, for the first time, the available data on the modern surgical treatment of valvular disease in hemophiliacs have been synthesized and systematized.

Changing hemostatic management in post-partum hemorrhage.

Early and fast assessment of hemostasis during postpartum hemorrhage (PPH) is essential to allow early characterization of coagulopathy, estimate bleeding severity and improve outcome. During PPH, fibrinogen decrease occurs earlier than other coagulation factors deficiency and hypofibrinogenemia is an early marker of PPH severity of progression. With good evidence in the context of PPH, point-of-care viscoelastic (VET) hemostatic assays have been shown to provide rapid assessment of hemostatic disorders, low fibrinogen levels, and allow VET-guided fibrinogen replacement. Further studies are needed to define the thresholds for the other coagulation parameters.

The identification of a novel compound heterozygous mutation in hereditary human coagulation factor VII deficiency following a bamboo leaf green snake bite.

Hereditary factor VII (FVII) deficiency is an uncommon autosomal recessive disorder associated with mutations in the F7 gene, and laboratory investigations usually reveal isolated prolongation in prothrombin time (PT)/international normalized ratio (INR). Venom-induced consumptive coagulopathy (VICC) is distinguished by the activation of the coagulation pathway, which is triggered by procoagulant toxins in snake venom. Diagnosing snakebites in patients with hereditary FVII deficiency presents a challenge because prolonged time PT/INR is considered the most valuable diagnostic method for VICC. Therefore, it is possible that certain patients may not promptly receive an accurate diagnosis of hereditary FVII deficiency. We present a pedigree featuring hereditary FVII deficiency, which was diagnosed through Sanger sequencing, following a bamboo leaf green snake bite.

Fidanacogene Elaparvovec (Beqvez)

&#x0D; CADTH recommends that Beqvez be reimbursed by public drug plans for the treatment of adults with moderately severe to severe hemophilia B (congenital factor IX deficiency) who are negative for neutralizing antibodies to variant adeno-associated virus (AAV) serotype Rh74 , if certain conditions are met.&#x0D; Beqvez should only be covered to treat adult patients (aged 18 years or older) with circulating coagulation factor IX (FIX:C) activity of 2% or less and bleeding that requires ongoing prophylactic treatment. Beqvez should not be covered if the patient has FIX inhibitors or has previously received gene therapy for hemophilia B.&#x0D; Beqvez should only be reimbursed if prescribed by specialists who have expertise in treating hemophilia B and if the cost of Beqvez is reduced. Beqvez is a 1-time therapy.&#x0D;

Causal Effects of COVID-19 on the Risk of Thrombosis: A Two-Sample Mendel Randomization Study.

Coronavirus disease 2019 (COVID-19) and thrombosis are linked, but the biomolecular mechanism is unclear. We aimed to investigate the causal relationship between COVID-19 and thrombotic biomarkers. We used two-sample Mendelian randomization (MR) to assess the effect of COVID-19 on 20 thrombotic biomarkers. We estimated causality using inverse variance weighting with multiplicative random effect, and performed sensitivity analysis using weighted median, MR-Egger regression and MR Pleiotropy Residual Sum and Outlier (MR-PRESSO) methods. All the results were examined by false discovery rate (FDR) with the Benjamin and Hochberg method for this correction to minimize false positives. We used R language for the analysis. All COVID-19 classes showed lower levels of tissue factor pathway inhibitor (TFPI) and interleukin-1 receptor type 1 (IL-1R1). COVID-19 significantly reduced TFPI (odds ratio [OR] = 0.639, 95% confidence interval [CI]: 0.435-0.938) and IL-1R1 (OR = 0.603, 95% CI = 0.417-0.872), nearly doubling the odds. We also found that COVID-19 lowered multiple coagulation factor deficiency protein 2 and increased C-C motif chemokine 3. Hospitalized COVID-19 cases had less plasminogen activator, tissue type (tPA) and P-selectin glycoprotein ligand 1 (PSGL-1), while severe cases had higher mean platelet volume (MPV) and lower platelet count. These changes in TFPI, tPA, IL-1R1, MPV, and platelet count suggested a higher risk of thrombosis. Decreased PSGL-1 indicated a lower risk of thrombosis. TFPI, IL-1R, and seven other indicators provide causal clues of the pathogenesis of COVID-19 and thrombosis. This study demonstrated that COVID-19 causally influences thrombosis at the biomolecular level.

Identification of a murder caused by brodifacoum poisoning based on clinical examinations and LC-MS/MS results.

Brodifacoum exerts its antagonistic effect against the metabolism of vitamin K, an essential component in the synthesis of blood coagulation factors. This effect ultimately hinders the blood's capacity to clot effectively, rendering it a commonly employed rodenticide. Instances of lethal poisonings are exceedingly rare owing to expeditious medical intervention and treatment. Within this report, we present a case of brodifacoum-induced homicide, wherein the patient exhibited distinct clinical examinations and symptoms. Moreover, the patient's blood sample exhibited a noteworthy brodifacoum concentration of 0.681µg/mL even after a period of 43 days following the incident of poisoning. Although an autopsy was not conducted due to religious restrictions, we endeavor to reasonably deduce the cause of death and furnish corroborative evidence for clinical diagnosis, treatment, and forensic examination in instances involving brodifacoum poisoning.