Von Willebrand Research Articles

The association of pre-operative biomarkers of endothelial dysfunction with the risk of post-operative neurocognitive disorders: results fromthe BioCog study.

Endothelial dysfunction (ED) promotes the development of atherosclerosis, and studies suggest an association with age-related neurocognitive disorders. It is currently unclear whether ED is also associated with the risk of perioperative neurocognitive disorders. We included 788 participants aged ≥ 65 years of the BioCog study. Patients were scheduled to undergo elective surgery with expected duration > 60 min. Blood was collected before surgery for measurement of 5 biomarkers of ED: asymmetric and symmetric dimethylarginine (ADMA; SDMA), intercellular and vascular adhesion molecule (ICAM-1, VCAM-1), and von Willebrand factor (vWF). Patients were monitored for the occurrence of postoperative delirium (POD) daily until the 7th postoperative day. 537 (68.1%) patients returned for a 3-month follow-up. Post-operative cognitive dysfunction (POCD) was defined from the change in results on a battery of 6 neuropsychological tests between baseline and 3 months, compared to the change in results of a control group during the 3-month interval. The associations of each of the 5 ED biomarkers with POD and POCD respectively were determined using multiple logistic regression analyses with adjustment for age, sex, surgery type, pre-morbid IQ, body mass index,hypertension, diabetes,HbA1C, triglyceride, total and HDL cholesterol. 19.8% of 788 patients developed POD; 10.1% of 537 patientshad POCDat 3 months. Concentrations of ED biomarkers were not significantly associated with a POD. A higher VCAM-1 concentration was associated with a reduced POCD risk (adjustedodds ratio 0.55; 95% CI: 0.35-0.86). No further statistically significant results were found. Pre-operative concentrations of ED biomarkers werenot associated with POD risk. We unexpectedly found higher VCAM-1 to be associated with a reduced POCD risk. Further studies are needed to evaluate these findings.

8042 A Rare Case of Papillary Thyroid Carcinoma in a Patient with Li-Fraumeni Syndrome

Abstract Disclosure: K.M. Bakhtawar: None. G. Jaiswal: None. Li-Fraumeni syndrome (LFS) is an autosomal dominant syndrome with a high lifetime probability of cancer at an early age. The spectrum of cancers primarily includes osteosarcoma, soft tissue sarcoma, breast cancer, brain tumors, leukemia, and Adenoid cystic carcinoma. Prior studies have estimated the cumulative cancer risk to be about 50% by age 40 and as high as 90% by age 60. As screening for TP53 mutations has improved and more patients are identified, the LFS cancer spectrum has expanded to include thyroid cancer. However, the occurrence of thyroid cancer in LFS has not been extensively assessed in the literature. A recent study examined cancer patients carrying the Brazilian p.R337H TP53 mutation which demonstrated that out of 101 patients, 11 had thyroid cancer (10.9%). In our case, a 45-year-old female with a past medical history of Li-Fraumeni syndrome, Von Willebrand disease, Pulmonary embolism, HER-2 positive invasive ductal carcinoma of the left breast status post chemotherapy, and bilateral mastectomy presented for evaluation of papillary thyroid carcinoma (PTC). An enlarged thyroid was initially identified on physical exam by the PCP with a follow-up thyroid ultrasound showing bilateral nodules. The right upper pole 1.9 x 1.3 x 1.6 cm nodule was biopsied revealing PCT. Following neck ultrasound demonstrated mildly enlarged lymph nodes on the right side, level 2A 1.5 cm and level 3 1.6 cm. The patient subsequently underwent total thyroidectomy and lymph node dissection. The pathology report revealed a 1.4 cm PTC in the upper right pole, a 0.9 cm PCT in the isthmus, and a 0.8 cm PTC in the left midpole. 4/62 lymph nodes were positive with the largest deposit of 1 cm. All margins were negative for carcinoma with no angioinvasion or lymphatic invasion. She was staged as T1bN1bM0. We are awaiting post-operative Thyroglobulin level to assess the need for Radioactive iodine. BRAFV600E and P53 mutation was identified. The patient carries known heterozygous mutation p.R1755H in the TP53 gene with an estimated lifetime cancer risk of 93%. This particular mutation has not been associated with thyroid cancer in prior studies. Although thyroid cancer is an uncommon manifestation of LFS, this case begs the importance of further studies to explore this association which may then lead to early screening and treatment of thyroid cancer in individuals with founder TP53 mutations. Presentation: 6/1/2024

8254 The Risk Of Thrombotic Complications In Patients With Post-COVID Syndrome Is High Even With Normal Coagulogram Values

Abstract Disclosure: A. Alieva: None. The high risk of thrombotic complications in patients with diabetes, even more increased in the post-Covid period, requires practicing physicians to be especially vigilant and carefully monitor the state of the hemostatic system and the function of the vascular endothelium. Routine laboratory tests may be insufficient for dynamic monitoring and timely detection of abnormalities. In this article, the author proposes the determination of cell adhesion molecules as a predictor of thrombotic complications in patients with type 2 diabetes mellitus in the post-Covid period. In our current study, VCAM-1 levels were elevated in all patients with type 2 diabetes within 24 months of COVID-19 infection and were not associated with increased von Willebrand factor or D-dimer or other coagulation abnormalities. This means that routine determination of coagulogram, D-dimer and von Willebrand factor may miss the stage of prothrombotic changes in the microvasculature. It is possible that an increase in the level of cell adhesion molecules precedes the appearance of other abnormalities in the hemostasiogram. Therefore, for patients with type 2 diabetes after a coronavirus infection with normal coagulogram values, it seems promising to determine the level of VCAM-1 molecules to prevent the occurrence of thrombotic complications. In addition, monitoring this indicator may be useful in determining the effectiveness of preventive therapy. Presentation: 6/3/2024

Von Willebrand factor exacerbates heart failure through formation of neutrophil extracellular traps.

Heart failure (HF) is a leading cause of mortality worldwide and characterized by significant co-morbidities and dismal prognosis. Neutrophil extracellular traps (NETs) aggravate inflammation in various cardiovascular diseases; however, their function and mechanism of action in HF pathogenesis remain underexplored. This study aimed to investigate the involvement of a novel VWF-SLC44A2-NET axis in HF progression. NET levels were examined in patients with HF and mouse models of transverse aortic constriction (TAC) HF. PAD4 knockout mice and NET inhibitors (GSK-484, DNase I, NEi) were used to evaluate the role of NETs in HF. RNA sequencing was used to investigate the downstream mechanisms. Recombinant human ADAMTS13 (rhADAMTS13), ADAMTS13, and SLC44A2 knockouts were used to identify novel upstream factors of NETs. Elevated NET levels were observed in patients with HF and TAC mouse models of HF. PAD4 knockout and NET inhibitors improved the cardiac function. Mechanistically, NETs induced mitochondrial dysfunction in cardiomyocytes, inhibiting mitochondrial biogenesis via the NE-TLR4-mediated suppression of PGC-1α. Furthermore, VWF/ADAMTS13 regulated NET formation via SLC44A2. Additionally, sacubitril/valsartan amplifies the cardioprotective effects of the VWF-SLC44A2-NET axis blockade. This study established the role of a novel VWF-SLC44A2-NET axis in regulating mitochondrial homeostasis and function, leading to cardiac apoptosis and contributing to HF pathogenesis. Targeting this axis may offer a potential therapeutic approach for HF treatment.

8241 Post-Covid complications in patients with diabetes mellitus are high during 24 month after acute infection

Abstract Disclosure: A. Alieva: None. The consequences of coronavirus infection in patients with diabetes have not been fully studied. The purpose of the work was to study post-Covid complications in patients with diabetes. Materials and methods. We examined 188 patients with diabetes mellitus who had a coronavirus infection in 2020 and applied to the RSSPMCE clinic for inpatient treatment within 1-24 months after the acute period of viral infection. The criteria for inclusion in the study were: the presence of type 2 diabetes mellitus (DM), diagnosed before 2020, a history of COVID-19 infection confirmed by PCR. Exclusion criteria were pregnancy and diabetes diagnosed in 2020 and later. Results and discussion. An increase in D-dimer levels was observed at 0-3, 7-9 and 19-24 months, which was accompanied by an increase in von Willebrand factor at 4-9 months and thrombosis at 4-6 months after COVID-19. The period of 4-6 months after coronavirus infection was also characterized by an increase in inflammatory markers and the development of purulent complications. The progression of polyneuropathy was noted during the first 6 months after COVID-19; for periods of 6-12 months, the development of vasculitis was typical. In the periods of 1-3 months and 10-24 months after COVID-19, cases of the development of newly registered hypertension were observed. Conclusion. Patients with type 2 diabetes mellitus for 2 years after coronavirus infection remain at risk of developing thrombotic complications, new-onset arterial hypertension and accelerated progression of chronic complications of diabetes mellitus, which requires careful targeted monitoring of such patients. Presentation: 6/3/2024

A novel snake venom C-type lectin-like protein modulates blood coagulation by targeting von Willebrand factor and coagulation factor IX

Snake venom C-type lectin-like proteins (CLPs) belong to the nonenzymatic proteins. To date, no CLP with both platelet and coagulation factors activating activities has been reported. In this study, a novel CLP, termed protocetin, with molecular weight of 29.986 kDa, was purified from the Protobothrops mucrosquamatus venom (PMV). It consists of α- and β-chains, with 67% similarity in their N-terminal sequence. Protocetin activates glycoprotein Ib (GPIb) by binding to von Willebrand factor (vWF), inducing platelet aggregation. It also activates the intrinsic coagulation pathway by binding to coagulation factor IX. After injection of protocetin into mice at dose of 0.5 µg/g or 1.5 µg/g, it resulted in activation of platelets, a notable reduction in platelet count and prolonged tail bleeding time. Additionally, the plasma activated partial thromboplastin time (APTT) was significantly extended, and the fibrinogen concentration was markedly reduced. Thrombelastogram comfirmed the anticoagulation effect of protocetin. Notably, no microthrombosis was observed in tissues of lung, liver and kidney within 1 h after injection of protocetin into the mice at dose of 0.5 µg/g. This study revealed protocetin as a novel CLP from PMV that has dual functions in activating platelet and coagulation factor IX, thereby modulates coagulation in vivo. This work contributes to a better understanding of the structure and function of snake venom CLP.

Pregnancy loss in individuals with von Willebrand disease and unspecified mucocutaneous bleeding disorders: A multicentre cohort study

BackgroundWhile bleeding around pregnancy is well described in von Willebrand disease (VWD), risk of pregnancy loss is less certain. We aimed to describe the frequency of pregnancy loss in females with VWD, compared with those with a similar mucocutaneous bleeding phenotype and no VWD, or compared with non-bleeding disorder controls. MethodsFemale patients were consecutively approached in 8 specialty bleeding disorder clinics between 2014-2023. The VWD group was defined as having VWF:Antigen (Ag) and VWF:Activity (Act) levels, each <0.50 IU/mL on ≥2 occasions, and a Condensed MCMDM-1 score of ≥4. The non-VWD mucocutaneous bleeding disorder group had VWF levels ≥0.50 IU/mL on ≥2 occasions and a MCMDM-1 score ≥4. A non-bleeding disorder control group was recruited in pregnancy from a low-risk maternity clinic. ResultsThere were 150 females in the VWD group, 145 in the non-VWD mucocutaneous bleeding disorder group, and 137 in the control group. There was a similar frequency of individuals with ≥1 loss in the VWD group (45.3%, 68/150), the non-VWD group (56.6%, 82/145) (-11.2%, 97.5% CI -24.2, 1.8%), and the non-bleeding disorder control group (37.2%, 51/137) (8.1%, 97.5% CI -4.9%, 21.1%). Using a logistic regression, the odds ratio of pregnancy losses in the VWD group versus non-VWD group was 0.94 (95% CI 0.65, 1.36). All groups experienced more recurrent losses compared to the literature. ConclusionsThere was no statistically significant difference in risk of pregnancy loss between females with VWD, females with a similar mucocutaneous bleeding phenotype, and with non-bleeding disorder controls.

Staged Retrograde Intraoperative Enteroscopy: Description of the 5-Step Surgical Technique for the Diagnosis and Treatment of Small Bowel Bleeding.

Background: Small bowel bleeding (SB) comprises 5%-10% of gastrointestinal (GI) bleeding cases. This article describes the staged retrograde intraoperative enteroscopy (SRIE) surgical technique for the etiological diagnosis and treatment of small bowel bleeding. Methods: SRIE was performed on patients with persistent SB at a quaternary university hospital in Brazil from 2020 to 2023. The technique is described in 5 steps, alongside visual aids, including images and a depicting a portion of the procedure. Patients presenting with confirmed coagulopathies, pregnancy, or unwillingness for surgery were excluded. Surgical procedures were performed after informed consent. Case Series: Four participants were submitted to SRIE, including 2 females (64 and 83 years old), and 2 males (46 and 57 years old). Three out of four (75%) of the patients received a confirmed diagnosis of GI bleeding, attributed to angioectasia, acquired von Willebrand disease, and vitamin K deficiency. SRIE was conducted via enterotomy, involving a subsequent insufflation-inspection-deflation of 10 to 10 cm segments of the small bowel (Steps 1 to 5). The procedure was successfully executed in all four patients without complications, allowing confirmation of the etiological diagnosis of SB or exclusion of anatomical causes of hemorrhage. Conclusions: SRIE is a valuable but invasive tool for assessing SB hemorrhage when conventional imaging falls short. When performed systematically and standardized, it allows accurate visualization of SB using a standard endoscope.

AKI as the Initial Presentation of Polycythemia Vera with von Willebrand Disease in a Young Adult

AKI as the Initial Presentation of Polycythemia Vera with von Willebrand Disease in a Young Adult

Undiagnosed Von Willebrand Disease Detected after Dermal Filler

Undiagnosed Von Willebrand Disease Detected after Dermal Filler

Pharmacokinetic Study of Coagulation Factor Ⅷ in Adults with Severe Hemophilia A

To detect the pharmacokinetic (PK) parameters of coagulation factor Ⅷ (FⅧ) in adult patients with severe hemophilia A, identify the potential factors influencing FⅧ PK, and optimize the use of FⅧ in individual prophylaxis regimens. PK characteristics of FⅧ were studied in a total of 23 severe hemophilia A adults. The correlation of patients' characteristics including age, von Willebrand factor antigen (vWF:Ag), blood group, weight, body mass index (BMI) and FⅧ genotype, with FⅧ PK were evaluated. Individual prophylaxis regimens were given based on FⅧ PK parameters. The mean terminal half‑life (t1/2) of FⅧ was 20.6±9.3 h, ranged from 11.47 h to 30.12 h. The age (r =0.580) and vWF:Ag (r =0.814) were significantly positively correlated with t1/2 of FⅧ. The mean area under the plasma concentration curve (AUC) of FⅧ was 913±399 (328-1 878) IU·h/dl, and the AUC of FⅧ was positively correlated with age (r =0.557) and vWF:Ag (r =0.784). The mean residence time (MRT) of FⅧ was 24.7±12.4 (13.2-62.2) h, and the MRT of FⅧ was positively correlated with age (r =0.664) and vWF:Ag (r =0.868). The mean in vivo recovery (IVR) of FⅧ was 2.59±0.888 (1.5-4.29) IU/dl per IU/kg, the mean clearance (CL) of FⅧ was 3±1.58（0.97-7.18）ml/(kg·h)，and there was no significant correlation of IVR and CL with age and vWF:Ag. According to the individual PK parameters, ultra low-dose, low-dose and moderate-dose FⅧ were applied to 15, 6, 2 adults patients with severe hemophilia A for prophylaxis, respectively. There are significant individual differences in the FⅧ half-life of adult patients with severe hemophilia A. The older the patient, the higher the vWF:Ag level, and the longer the FⅧ half-life. Individual administration is required based on the FⅧ PK parameters to optimize prophylaxis treatment.

PROGRESSIVE SYSTEMIC INFLAMMATION PRECEDES DECOMPENSATION IN COMPENSATED CIRRHOSIS

Background & AimsSystemic inflammation is a driver of decompensation in cirrhosis with unclear relevance in the compensated stage. We evaluated inflammation and bacterial translocation markers in compensated cirrhosis and their dynamics in relation to the first decompensation. MethodsThis study is nested within the PREDESCI trial, which investigated non-selective beta-blockers for preventing decompensation in compensated cirrhosis and clinically significant portal hypertension (CSPH; HVPG≥10mmHg). Blood biomarkers were measured at baseline and at 1 and 2 years in patients who remained compensated and had available samples (n=164). Values of patients with CSPH were split at each time point by decompensation development in the next time interval after sampling. We also included 54 patients with cirrhosis and subclinical portal hypertension (PH) and 35 controls. We assessed inflammation markers (interleukin-6 [IL-6], tumor necrosis factor-alpha, von Willebrand factor [vWF], C-reactive protein), macrophage activation (CD14, CD163), intestinal barrier integrity (fatty acid-binding protein [FABP], haptoglobin), and bacterial translocation (lipopolysaccharide [LPS]). ResultsIL-6, CD163, and vWF were higher (p<0.01) at baseline in patients with cirrhosis and CSPH compared to those with subclinical PH and controls. IL-6 increased (p<0.05) at 1-year in CSPH patients, with a greater rise in those who developed decompensation. CD163 was higher (p<0.01) in patients who decompensated at baseline and 1- and 2-year. FABP was elevated (p<0.01) in CSPH patients compared to subclinical PH and controls at baseline and 1 year, while haptoglobin was lower (p<0.01). LPS was higher (p<0.01) in CSPH patients than in those with subclinical PH and controls and increased at 1-year regardless of decompensation development. ConclusionsInflammation and bacterial products are present in the systemic circulation in compensated cirrhosis with CSPH. Progressive inflammation precedes the first decompensation.

Keep it positive: loss of positive charge induced by R1205H von Willebrand factor change accelerates von Willebrand factor clearance through enhanced binding to macrophage clearance receptors LRP1 and SR-A1

Keep it positive: loss of positive charge induced by R1205H von Willebrand factor change accelerates von Willebrand factor clearance through enhanced binding to macrophage clearance receptors LRP1 and SR-A1

Dynamic conformational response of von Willebrand factor to varying shear stress: A hybrid computational approach

This computational study examines the mechanobiological responses of von Willebrand Factor (vWF) to different shear stress levels, emphasizing the unique structural dynamics of its various domains. We introduce a novel coarse-grained model, representing each cluster of six amino acids as a bead, to synthesize the Lattice Boltzmann method with Brownian dynamics. This approach captures the vWF molecule’s conformational adaptability across a spectrum of shear rates, ranging from 5 to 5e + 7s−1, encompassing normal physiological flows to those resembling the high-shear environment of arterial stenosis.Our results reveal domain-specific responses of vWF, particularly in the A2 and A3 domains, which demonstrate significant elongation under elevated shear—reflecting their pivotal roles in clotting processes. Moreover, the study underscores the critical influence of random thermal forces on the molecule’s conformation, with simulations including these forces showing substantially greater conformational variability compared to those without.As shear rates increase, we observe a notable reorganization in the spatial arrangement of vWF domains. This reconfiguration is most evident in the increased separation between the A1 and D’D3 domains under high shear conditions, potentially enhancing the accessibility of platelets to key binding sites on vWF. These findings are paramount for a deeper understanding of vWF’s mechanical behavior in blood clotting and thrombosis, particularly the delicate balance between facilitating platelet adhesion and avoiding excessive stretching that could lead to thrombosis.Our work provides a foundation for future studies investigating vWF behavior in complex flow geometries and its interactions with other blood components. Such insights pave the way for more informed therapeutic strategies targeting vWF function in vascular health and disease, potentially leading to improved treatments for thrombotic disorders.

Cooperation between Coagulase and von Willebrand factor binding protein in Staphylococcus aureus fibrin pseudocapsule formation

The major human pathogen Staphylococcus aureus forms biofilms comprising of a fibrin network that increases attachment to surfaces and shields bacteria from the immune system. It secretes two coagulases, Coagulase (Coa) and von Willebrand factor binding protein (vWbp), which hijack the host coagulation cascade and trigger the formation of this fibrin clot. However, it is unclear how Coa and vWbp contribute differently to the localisation and dynamics of clot assembly in growing biofilms.Here, we address this question using high-precision time-resolved confocal microscopy of fluorescent fibrin to establish the spatiotemporal dynamics of fibrin clot formation in functional biofilms. We also use fluorescent fusion proteins to visualise the locations of Coa and vWbp in biofilms using both confocal laser scanning and high resolution highly inclined and laminated optical sheet microscopy. We visualise and quantify the spatiotemporal dynamics of fibrin production during initiation of biofilms in plasma amended with fluorescently labelled fibrinogen.We find that human serum stimulates coagulase production, and that Coa and vWbp loosely associate to the bacterial cell surface. Coa localises to cell surfaces to produce a surface-attached fibrin pseudocapsule but can diffuse from cells to produce matrix-associated fibrin. vWbp produces matrix-associated fibrin in the absence of Coa, and furthermore accelerates pseudocapsule production when Coa is present. Finally, we observe that fibrin production varies across the biofilm. A sub-population of non-dividing cells does not produce any pseudocapsule but remains within the protective extended fibrin network, which could be important for the persistence of S. aureus biofilm infections as antibiotics are more effective against actively growing cells.Our findings indicate a more cooperative role between Coa and vWbp in building fibrin networks than previously thought, and a bet-hedging cell strategy where some cells produce biofilm matrix while others do not, but instead assume a dormant phenotype that could be associated with antibiotic tolerance.

Isolation-protocol, characterization, and in-vitro performance of equine umbilical vein endothelial cells.

Angiogenesis plays a crucial role in various physiological and pathological conditions. However, research in equine angiogenesis is relative limited, necessitating the development of suitable in-vitro models. To effectively analyze angiogenesis in-vitro, it is essential to target the specific cells responsible for this process, namely endothelial cells. Human umbilical vein endothelial cells (HUVECs) are one of the most used in vitro models for studying angiogenesis in humans. Serving as an equivalent to HUVECs, we present a comprehensive isolation protocol for equine umbilical vein endothelial cells (EqUVECs) with relatively minimal requirements, thereby enhancing accessibility for researchers. Umbilical cords obtained from five foals were used to isolate endothelial cells, followed by morphological and immunohistochemical identification. Performance of the cells in various assays commonly used in angiogenesis research was studied. Additionally, EqUVEC expression of vascular endothelial growth factor (VEGF) was assessed using ELISA. EqUVECs exhibited endothelial characteristics, forming a homogeneous monolayer with distinctive morphology. Immunohistochemical staining confirmed positive expression of key endothelial markers including von Willebrand factor (vWF), CD31, and vascular endothelial growth factor receptor-2 (VEGFR-2). Furthermore, performance assessments in in-vitro assays demonstrated the viability, proliferation, migration, tube formation and VEGF-expression capabilities of EqUVECs. The findings suggest that EqUVECs are a promising in-vitro model for studying equine angiogenesis, offering a foundation for further investigations into equine-specific vascular processes and therapeutic interventions.

Evaluating the Role of Silymarin in Coordinating the Relationship between Inflammation and Thrombosis by Affecting Endothelial Cells

Background: A widespread crosstalk between inflammation and coagulation has been shown in numerous studies. This suggests that coagulation can trigger an inflammatory response which ultimately leads to coagulation activation. Previous research has shown that polyphenols can affect blood pressure and endothelial dysfunction, resulting in reduced risk of cardiovascular diseases. This study aimed to investigate whether Silymarin, a flavonolignans, could play a role in the interaction between inflammation and coagulation by influencing endothelial cells. Materials and Methods: In this experimental study, human umbilical vein endothelial cells (HUVECs) were seeded with and without various concentrations of silymarin. In vivo, treatment with silymarin was also carried out. Coagulative and fibrinolytic factors, including Von Willebrand factor (VWF) and Factor VIII (FVIII), tissue plasminogen activator-1 (TPA-1), and inflammatory factors, including interleukin 8 (IL-8) and tumor necrosis factor-alpha (TNF-α), were evaluated by flow cytometry, Real-Time Polymerase Chain Reaction (qPCR), Enzyme-Linked Immunosorbent Assay (ELISA) and Immunocytochemistry (ICC). Results: Silymarin increased the gene expression, release, and storage of VWF while diminishing the gene expression, release, and storage of TPA-1 (P ˂ 0.05). The activity of FVIII was dramatically increased, and IL-8 and TNF-α levels were augmented. The in vivo study also indicated an elevated plasma level of VWF and IL-8 by silymarin administration. Conclusion: The results showed that, although silymarin reduces inflammatory factors, it can affect coagulation factors by increasing the levels of VWF and FVIII activity and inhibiting TPA-1 production, thereby making thrombosis probable. Consequently, it is advisable to prescribe this medication with caution for individuals who are susceptible to thrombotic events.

Identifying clinical and proteomic markers for early diagnosis and prognosis prediction of major psychiatric disorders

BackgroundTo clarify if blood proteins can predict disease progression among individuals at clinical high-risk of severe mental illness (CHR-SMI), we developed a statistical model incorporating clinical and blood protein markers to distinguish the transition group (who developed severe mental illness) (CHR-SMI-T) and from non-transition group (CHR-SMI-NT) at baseline. MethodsNinety individuals (74 at CHR-SMI: 16 patients) were monitored for ≤4 years and were the focus of predictive models. Three predictive models (1 [100 clinical variables], 2 [158 peptides], and 3 [100 clinical variables +158 peptides]) were evaluated using area under the receiver operating characteristic (AUROC) values. Clinical and protein feature patterns were evaluated by linear mixed-effect analysis within the model at 12 and 24 months among patients who did (CHR-SMI-T) and did not transition (CHR-SMI-NT) and the entire group. ResultEighteen CHR-SMI individuals with major psychiatric disorders (first episode psychosis: 2; bipolar II disorder: 13; major depressive disorder; 3) developed disorders over an average of 17.7 months. The combined model showed the highest discriminatory performance (AUROC = 0.73). Cytosolic malate dehydrogenase and transgelin-2 levels were lower in the CHR-SMI-T than the CHR-SMI-NT group. Complement component C9, inter-alpha-trypsin inhibitor heavy chain H4, von Willebrand factor, and C-reactive protein were lower in the patient than the CHR-SMI-NT group. These differences were non-significant after FDR adjustment. LimitationsSmall sample, no control for medication use. ConclusionThis exploratory study identified clinical and proteomic markers that might predict severe mental illness early onset, which could aid in early detection and intervention. Future studies with larger samples and controlled variables are needed to validate these findings.

Comparative Analysis of Coagulation Activation in Rheumatoid Arthritis Patients Treated With TNF Inhibitors Versus JAK Inhibitors: A Prospective Study.

This study aims to investigate the activation of the coagulation system of RA patients and assess changes during anti-inflammatory treatment with tumor necrosis factor blockers (anti-TNF) and Janus kinase inhibitors (JAKi). Biomarkers for the coagulation system, including D-dimer, fibrinogen, prothrombin time, activated partial thrombin time, prothrombin fragment 1 + 2, thrombin-antithrombin complex (TAT), activated factor IX, antithrombin complex, and von Willebrand factor (vWF), were longitudinally measured in 83 RA patients treated with anti-TNF and 38 RA patients with JAKi. Data were collected at baseline, after 1, 3, and 6 months. The mean age was 57 (±14) years; 76% was female. The mean DAS28-CRP was 3.6 (±1.3) for anti-TNF users and 4.1 (±1.4) for JAKi users at baseline and declined in both groups. Baseline coagulation markers levels were comparable between groups. In anti-TNF users, D-dimer and fibrinogen levels significantly declined (-0.31 mg/L, p = 0.01 and -0.71 g/L, p < 0.001, respectively), whereas TAT significantly increased after 6 months follow-up (1.46 μg/L, p = 0.03) and no effect on vWF (p = 0.98). In JAKi users, vWF declined significantly during the 6 months follow-up (-37.41%, p < 0.001); additionally, there were reductions of D-dimer, fibrinogen, and TAT that did not reach significance (-0.17 mg/L, p = 0.59; -0.49 g/L, p = 0.12; and 0.68 μg/L, p = 0.27, respectively). The prothrombotic tendency in active RA declined during effective treatment with both anti-TNF and JAKi. Altogether, the biomarkers used in this study suggest that an increased VTE risk in the first 6 months due to either treatment with anti-TNF or JAKi is unlikely.

Von Willebrand disease: a key to understanding nosebleeds in men

Von Willebrand disease: a key to understanding nosebleeds in men