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- | Journal: Neutrophil extracellular traps, platelets and endothelial cells cooperatively contribute to hypercoagulability in non-small-cell lung cancer. (Pubmed Central) - Nov 30, 2024
Our results suggest that NETs contribute to hypercoagulability and may represent a potential therapeutic target to prevent cancer-associated thrombosis in NSCLC patients.
- | Biomarker, Journal: Prevalence and Risk Factors of Pulmonary Embolism in COPD Patients Complicated with Secondary Polycythemia. (Pubmed Central) - Nov 15, 2024
In COPD patients with SP, routine joint detection of blood and cardiac markers, blood gas analysis, and pulmonary function tests can help to identify patients with PE. APC, u-PA, TF, FKN, TM, and IL-38 are risk factors for PE in patients with COPD and SP, and clinical treatment can effectively reduce this risk.
- | Afstyla (lonoctocog alfa) / CSL Behring, Advate (octocog alfa) / Takeda
Journal: Comprehensive laboratory assessment of lonoctocog alfa versus octocog alfa in severe haemophilia A. (Pubmed Central) - Nov 13, 2024
Lonoctocog alfa and octocog alfa showed comparable recovery and safety in vivo as well as similar impacts on TG in vitro. Observed assay discrepancies on lonoctocog alfa demonstrated variability of results also between different FVIII CSAs.
- A Novel In Vivo Model to Study the Role of Excess FVIII Function in Venous Thrombosis (Halls G-H (San Diego Convention Center)) - Nov 6, 2024 - Abstract #ASH2024ASH_4108;
These data support that the 2% FeCl3 femoral vein injury model is sensitive to excess FVIII function and the impact of APC on FVIIIa regulation, and suggests this model may be used to study FVIII-associated prothrombotic risk in vivo. Long-term, we aim to employ this model to elucidate the mechanisms by which excess FVIII confers prothrombotic risk and to inform a therapeutic window of gain-of-function FVIII variants that bypass mechanisms of FVIIIa-regulation for second-generation hemophilia A gene therapy approaches.
- A Novel Factor VIII Mutation with Increased Activity, Severe Thrombosis and Resistance to Activated Protein C (Room 28 A-D (San Diego Convention Center)) - Nov 6, 2024 - Abstract #ASH2024ASH_2501;
The mutation confers highly increased FVIII activity. Our studies suggest that R590S FVIII activates thrombin rapidly and is not responsive to APC.
- | Journal: Divergent Modulation of Activated Protein C Pleiotropic Functions by Antibodies That Differ by A Single Amino Acid. (Pubmed Central) - Oct 29, 2024
This study illustrates that APC is highly sensitive to non-active site targeting that can lead to unpredictable changes in its activity profile of this pleiotropic enzyme. Further, this study demonstrates the ability to modify APC functions to advance the potential development of APC targeted antibodies as therapeutics for the treatment of diseases including trauma bleeding, hemophilia, ischemia, and sepsis.
- | Journal: Hepatocyte-independent PAR1-biased signaling controls liver pathology in experimental obesity. (Pubmed Central) - Oct 27, 2024
Further, this study demonstrates the ability to modify APC functions to advance the potential development of APC targeted antibodies as therapeutics for the treatment of diseases including trauma bleeding, hemophilia, ischemia, and sepsis. The results suggest that nonhepatocellular canonical PAR1 cleavage drives MASLD in obese mice and provide translational proof-of-concept that selective pharmacologic modulation of PAR1 yields multiple metabolic benefits in experimental obesity.
- Administration of the Recombinant Activated Protein C Rescues the Cardiac Vulnerability to Ischemic Insults in Aging through Modulating Inflammatory Response during Ischemia and Reperfusion (Zone 2' Moderated Digital Poster 5) - Oct 7, 2024 - Abstract #AHA2024AHA_6729;
- || Donesta (estetrol) / Mithra, Pantarhei
Clinical, Journal: Impact of Estetrol Combined with Drospirenone on Blood Coagulation and Fibrinolysis in Patients with Endometriosis: A Multicenter, Randomized, Open-Label, Active-Controlled, Parallel-Group Study. (Pubmed Central) - Sep 27, 2024
Eventually, the fibrinolysis cascade was triggered to compensate for disturbed coagulation, and D-dimer levels were 4.7-fold higher in the EE/DRSP group than in the E4/DRSP group. This study demonstrated that the effect of E4/DRSP on the blood coagulation and fibrinolysis cascades was significantly less than that of EE/DRSP in participants with endometriosis, a disease of women of advanced and reproductive age (jRCT2080225090, https://jrct.niph.go.jp/en-latest-detail/jRCT2080225090).
- | Journal: Understanding the Difference between Type-I and Type-II Anti-Prothrombin Antibodies and their Effect on Activated Protein C Resistance. (Pubmed Central) - Sep 21, 2024
This study demonstrated that the effect of E4/DRSP on the blood coagulation and fibrinolysis cascades was significantly less than that of EE/DRSP in participants with endometriosis, a disease of women of advanced and reproductive age (jRCT2080225090, https://jrct.niph.go.jp/en-latest-detail/jRCT2080225090). No abstract available
- | Journal: Heparins May Not Be the Optimal Anticoagulants for Sepsis and Sepsis-Associated Disseminated Intravascular Coagulation. (Pubmed Central) - Sep 17, 2024
In summary, further research is warranted, despite the ongoing clinical use of heparin for sepsis and sepsis-associated DIC. Based on Japanese guidelines, antithrombin or recombinant thrombomodulin may be a preferable choice if they are accessible.
- | dabigatran etexilate / Generic mfg.
Journal: Protein S contributes to the paradoxical increase in thrombin generation by low-dose dabigatran in the presence of thrombomodulin. (Pubmed Central) - Sep 9, 2024
Protein S participated in the paradoxical enhancement of thrombin generation in normal plasma spiking with low concentrations of dabigatran. Increased thrombin generation at low dabigatran can be explained by reduced thrombin-thrombomodulin mediated APC formation and subsequent reduced FVa inactivation that is protein S-dependent.
- | rivaroxaban / Generic mfg.
Journal: Development of an assay using a modified coagulation factor V to measure protein S activity. (Pubmed Central) - Sep 8, 2024
Increased thrombin generation at low dabigatran can be explained by reduced thrombin-thrombomodulin mediated APC formation and subsequent reduced FVa inactivation that is protein S-dependent. An assay using the FVm substrate may be less susceptible to interference and provide a more accurate evaluation of plasma PS activity than clot-based assays.
- | Journal: Impact of soluble thrombomodulin and activated protein C on dynamic hemostatic function in trauma: a focus on thrombin generation and clot lysis. (Pubmed Central) - Sep 5, 2024
Despite increased circulating sTM levels, the overriding dynamic coagulation effects seen after injury are: (a) accelerated thrombin generation and (b) increased rates of fibrinolysis. We find no evidence for sTM as the major determinant of the coagulation changes seen in early TIC.
- | paclitaxel / Generic mfg.
Journal: Identification of endothelial protein C receptor as a novel druggable agonistic target for reendothelialization promotion and thrombosis prevention of eluting stent. (Pubmed Central) - Sep 1, 2024
The commercially available drug-eluting stent with limus (rapamycin, everolimus, etc.) or paclitaxel inhibits smooth muscle cell (SMC), reducing the in-stent restenosis, whereas damages endothelial cell (EC) and delays stent reendothelialization, increasing the risk of stent thrombosis (ST) and sudden cardiac death...Activation of EPCR protects against coating drugs-induced EC injury, inflammatory cell, or platelet adhesion onto the stent. The novel application formula for APC/rapamycin-combined eluting promotes stent reendothelialization and prevents ST.
- | Journal: Specific DNA aptamer-immobilized cryogel membranes as novel bioaffinity supports and their potential for the purification of activated protein C. (Pubmed Central) - Aug 27, 2024
Adsorption capacity was found to be 89.02?mg/g. Finally, NaCl revealed efficiency for APC desorption and the reuse of cryogels was successfully tested for ten cycles.
- || Review, Journal: Platelets at the intersection of inflammation and coagulation in the APC-mediated response to myocardial ischemia/reperfusion injury. (Pubmed Central) - Aug 15, 2024
By unraveling the pathways of platelets and APC in the inflammatory and coagulation cascades, this review summarizes the role of these vital mediators in the development and perpetuation of heart disease and the thromboinflammation-driven complications of cardiovascular disease. Furthermore, this review emphasizes the significance of the counteracting effects of platelets and APC and their combined role in disease states.
- | Jetrea (ocriplasmin) / Oxurion
Journal: Macrocyclic inhibitors targeting the prime site of the fibrinolytic serine protease plasmin. (Pubmed Central) - Aug 9, 2024
For inhibitor 28 of the second series, the co-crystal structure in complex with a Ser195Ala microplasmin mutant revealed the P2' residue adopts multiple conformations. Most polar contacts to plasmin and surrounding water molecules are mediated through the P1 tranexamoyl residue, whereas the bound conformation of the macrocycle is mainly stabilized by two intramolecular hydrogen bonds.
- | Hemlibra (emicizumab-kxwh) / Roche
Journal: Activated protein C resistance in the copresence of emicizumab and activated prothrombin complex concentrates. (Pubmed Central) - Aug 8, 2024
FII and FIXa in APCCs were key clotting factors for APC resistance in FVIIIdef plasma supplemented with emicizumab and APCCs. The APC resistance in persons with hemophilia A receiving emicizumab and APCC may contribute to venous thromboembolic events.
- | Preclinical, Journal: Magisetty J, Kondreddy V, Keshava S, et (Pubmed Central) - Aug 1, 2024
The APC resistance in persons with hemophilia A receiving emicizumab and APCC may contribute to venous thromboembolic events. No abstract available
- bleomycin / Generic mfg., nintedanib / Generic mfg., apixaban / Generic mfg.
BEYOND THROMBOSIS: INVESTIGATING FACTOR V LEIDEN'S ROLE IN INTERSTITIAL LUNG DISEASE (Convention Center Exhibit Hall: Poster Area 3) - Jul 31, 2024 - Abstract #CHEST2024CHEST_1474;
Implementing screening for genetic predispositions among ILD patients may facilitate risk stratification and tailor personalized therapeutic interventions. Additionally, the observed ILD in family, highlights the need for increased awareness and surveillance among at-risk relatives, given that more than 1 in 6 first-degree relatives of PF patients may have undiagnosed ILD.
- | Journal: Protein C Pretreatment Protects Endothelial Cells from SARS-CoV-2-Induced Activation. (Pubmed Central) - Jul 31, 2024
We also observed that the serum of severe COVID-19 had a significant amount of activated protein C that could protect endothelial cells from serum-induced activation. In conclusion, activated protein C protects endothelial cells from pro-inflammatory and pro-coagulant effects during exposure to the SARS-CoV-2 virus.
- | Journal: Mimicking activated protein C-progress by PARtnering peptides. (Pubmed Central) - Jul 26, 2024
In conclusion, activated protein C protects endothelial cells from pro-inflammatory and pro-coagulant effects during exposure to the SARS-CoV-2 virus. No abstract available
- | Journal: Met343Val mutation disrupts the shuttling of Trp380 leading to a low-activity conformer of activated protein C and causes thrombosis. (Pubmed Central) - Jul 26, 2024
No abstract available The M343V mutation in patients adversely affects the reactivity and/or folding of the active site as well as the binding of the physiological substrate to the protease, resulting in impaired protein C anticoagulant activity and ultimately leading to thrombosis.
- A NOVEL PEPTIDE CAN SIGNIFICANTLY IMPROVE PRECLINICAL OUTCOMES IN A MURINE DEXTRAN SULFATE SODIUM MODEL OF COLITIS (Science Lounge) - Jul 18, 2024 - Abstract #UEGW2024UEGW_1382;
These significant improvements were seen at 10mg/kg and 50mg/kg peptide. Similar improvements were observed during endoscopy and upon histological assessment.
- | Journal: Comparison of an Unlabeled Probe High-Resolution Melting Analysis Assay (HRMA) for Factor V Leiden 1691 G/A Mutation to a Fluorogenic 5' Nuclease PCR Hydrolysis Assay. (Pubmed Central) - Jul 1, 2024
Similar improvements were observed during endoscopy and upon histological assessment. Comparing the results of the unlabeled probe HRMA FVL assay with a real-time TaqMan probe end point genotyping assay resulted in 100% sensitivity and 100% specificity for both assays.
- | Preclinical, Journal: An orthosteric/allosteric bivalent peptide agonist comprising covalently linked protease activated receptor-derived peptides mimics in vitro and in vivo activities of activated protein C. (Pubmed Central) - Jun 30, 2024
Comparing the results of the unlabeled probe HRMA FVL assay with a real-time TaqMan probe end point genotyping assay resulted in 100% sensitivity and 100% specificity for both assays. The PAR-sequence-derived G10 peptide is a bivalent agonist that mimics APC's cytoprotective, anti-inflammatory, and endothelial barrier-stabilizing actions and APC's protection against endotoxemic mortality.
- | Journal: Activated Protein C is Neuroprotective and Mediates New Blood Vessel Formation and Neurogenesis After Controlled Cortical Impact: Corrigendum. (Pubmed Central) - Jun 17, 2024
The PAR-sequence-derived G10 peptide is a bivalent agonist that mimics APC's cytoprotective, anti-inflammatory, and endothelial barrier-stabilizing actions and APC's protection against endotoxemic mortality. No abstract available
- | Preclinical, Journal: Biased agonism of protease-activated receptor-1 regulates thrombo-inflammation in murine sickle cell disease. (Pubmed Central) - Jun 14, 2024
These findings highlight the potential benefit of reducing thrombin-dependent PAR1 activation while preserving APC-PAR1 signaling in SCD thromboinflammation. These results also suggest that pharmacological strategies promoting biased PAR1 signaling could effectively mitigate vascular complications associated with SCD.
- | 3K3A-APC / ZZ Biotech
Journal: Cytoprotective 3K3A-activated protein C and plasma: A comparison of therapeutics for the endotheliopathy of trauma. (Pubmed Central) - May 27, 2024
Our data shows that FP24, in a post-trauma environment, pre-treatment with 3K3A-aPC can potentially mitigate the EoT to a greater degree than FP24 with or without 3K3A-aPC. Although further exploration is needed, this represents a potentially ideal and perhaps superior therapeutic treatment for the dysregulated thromboinflammation of injured patients.
- | Preclinical, Journal: Genetic Upregulation of Activated Protein C Mitigates Delayed Effects of Acute Radiation Exposure in the Mouse Plasma. (Pubmed Central) - May 24, 2024
Moreover, restoration of plasma levels of some metabolites, including amino acids, citric acid, and hypoxanthine, in APCHi mice is indicative of APC-mediated protection from radiation injuries. With the help of these findings, the role of APC in plasma molecular events after acute ?-radiation exposure in a gender-specific manner can be established for the first time.
- Directed Evolution of An Antibody Specific for a Non-Active Site of Activated Protein C (APC) - Identification of Positions Within Each CDR for Selective Modulation of APC Pleiotropic Activities (210 A-D) - May 17, 2024 - Abstract #ISTH2024ISTH_2223;
With the help of these findings, the role of APC in plasma molecular events after acute ?-radiation exposure in a gender-specific manner can be established for the first time. Directed evolution resulted in 21 antibodies with improved KD
- Immune modulation by the endothelial protein C receptor (EPCR) in cancer progression (111 A-C) - May 17, 2024 - Abstract #ISTH2024ISTH_2222;
CD103+ DCs were slightly expanded in the TME, but similar in dLN of PyMT-EPCRfloxLysM-cre and control mice. However, progenitor and terminally exhausted T cells were reduced in myeloid cell EPCR-deficient mice.
- Effect of estetrol and drospirenone combination on blood coagulation and fibrinolysis in Japanese patients with endometriosis (Ballroom B2) - May 17, 2024 - Abstract #ISTH2024ISTH_2158;
Anticoagulant proteins, protein S and tissue factor pathway inhibitor were reduced following EE/DRSP, thereby activated protein C sensitivity ratio (ETP-based) was significantly increased by approximately 4-fold compared to E4/DRSP. Eventually, fibrinolysis was triggered to compensate for the disturbed coagulation and D-dimer levels which were increased in the EE/DRSP group but less in the E4/DRSP group (Figure) Conclusion(s) : VTE is a safety concern in COC users and aging is a risk factor.
- Activated protein C regulates aberrant thrombo-inflammatory CD4+ T cell activity in inflammatory bowel disease. (111 A-C) - May 17, 2024 - Abstract #ISTH2024ISTH_2125;
Confocal microscopy confirmed the presence of TF+CD4+CD3+ T-cells in the colons of both colitogenic mice and paediatric IBD patients during active disease. TF is typically expressed in an
- Influence of coagulation proteases on cognitive function (208 A-D) - May 17, 2024 - Abstract #ISTH2024ISTH_2091;
Surprisingly, we could show that the cognitive impairment in TMPro/Pro mice was restored when crossing the TMPro/Pro mouse with a mouse carrying a hyperactivatable protein C transgene (aPChigh, Fig.1; exemplary non-spatial object recognition test). Conclusion(s) : We suggest that loss of TM-function, as observed in vascular disease, may impair CNS function.
- VGA039 / Vega Therap
VGA039, a novel anti-Protein S antibody, enhances ex vivo coagulation with hemophilia A blood as assessed by thromboelastometry (Exhibition Hall) - May 17, 2024 - Abstract #ISTH2024ISTH_1654;
In an experimentally induced non-human primate model of von Willebrand disease featuring administration of caplacizumab and neutralizing anti-factor VIII antibody (FVIII nAb), VGA039 reduced bleeding time from mucosal cuts and prevented blood loss. The median age of the included people with hemophilia A was 28 (range 14
- Mutation Ter462GlnextTer17 introduces a tail to C-terminus of protein C and causes venous thrombosis (Exhibition Hall) - May 17, 2024 - Abstract #ISTH2024ISTH_1643;
APC-Ter462GlnextTer17 exhibited a decreased hydrolytic activity towards the chromogenic substrate S2366. APTT and FVa degradation assays showed that the anticoagulant activity of the mutant protein was markedly reduced both in the absence and presence of protein S. These results were also confirmed by the thrombin generation assay in purified and plasma-based assay systems.
- Endothelial activation of protein C is disproportionately impaired in hereditary protein C deficiency (Exhibition Hall) - May 17, 2024 - Abstract #ISTH2024ISTH_1530;
Functional PC levels ranged from 35.5-74.6% and were significantly lower as compared to controls. Levels of protein S, antithrombin, and coagulation factors in plasma did not differ between cohorts.
- Met343Val mutation attenuates flexibility of residue Trp380 and impairs anticoagulant function of protein C (Exhibition Hall) - May 17, 2024 - Abstract #ISTH2024ISTH_1517;
Genetic analysis revealed that the patients carried the same heterozygous mutation c.1153A>G, p. Met343Val in PROC (Figure 1A), which had never been reported before. Coagulation tests demonstrated that activation of mutant zymogen by thrombin-TM was slightly affected.
- A novel factor V compound heterozygous mutation associated with thrombosis (Y1961C; FV-Kanazawa, and 1982_1983del). (Exhibition Hall) - May 17, 2024 - Abstract #ISTH2024ISTH_1483;
But inactivation of FVa-Y1961C was delayed and FVa-Y1961C:C persisted at 50?60% of the initial level regardless of the existence of Protein S. FVIIIa was inactivated by APC with FV-WT to ?25% of the initial level at 20 minutes. However FVIIIa was remained to?50% in FV-Y1961C.
- Activated Protein C ameliorates diabetes induced atherosclerosis by sustaining efferocytosis (Exhibition Hall) - May 17, 2024 - Abstract #ISTH2024ISTH_1432;
aPC prevented glucose induced impairment of macrophage efferocytosis. Exposure of PBMCs isolated from diabetic patients to aPC ex vivo was sufficient to restore efferocytosis.
- 3K3A-APC / ZZ Biotech
Activated Protein C (Exhibition Hall) - May 17, 2024 - Abstract #ISTH2024ISTH_1430;
aPC mitigated shock-induced hyperuricemia via de-activation of the polyol pathway by restoring adenosine triphosphate (ATP) and urate levels. It maintained energy homeostasis and energy supply by stabilizing tricarboxylic acid (TCA) cycle, creatine phosphate shuttle, and glycolysis metabolites (Figure 1a).
- Pregnancy Induced Thrombosis: a clinical study. (Exhibition Hall) - May 17, 2024 - Abstract #ISTH2024ISTH_1116;
Samples from 8 patients have already been analyzed on TGT and nAPCsr (7 weeks n=3, 3 months n=7, 6 months n=6, and 9 months n=2). Preliminary results show a time-dependent increase of both TGT (Figure 1) and nAPCsr (Figure 2).
- Circulating soluble Mer increases with the gestational weeks and correlates with the reduced level of Protein S in uncomplicated pregnancy (Exhibition Hall) - May 17, 2024 - Abstract #ISTH2024ISTH_1108;
Otherwise, an unaltered Gas 6 levels and a lower trend of plasma sAxl levels were revealed during pregnancy, suggesting that Gas 6-Axl signaling is not activated in uncomplicated pregnancy. Possible roles of elevated sMer and sTyro3 in coagulation were further examined, and TGA revealed that soluble receptors dose-dependently competed for phospholipid binding, yet the rising level in normal pregnancy was tolerable to disrupt coagulation balance.
- Assessment of the thrombogenic potential of ovarian stimulation and in-vitro fertilization treatment (Exhibition Hall) - May 17, 2024 - Abstract #ISTH2024ISTH_1093;
ETP of G1 was significantly higher at T3 (1687nM.min, 1364-2447%) compared to T1 (1035nM.min 865.0-1373%), p=0.001, and compared to T2 (1330nM.min, 992.0-1519%), p=0.05. APCr with rhAPC was greater at T3 in both G1 (61.17%, 36-102.6%) and G2 (52.04%, 2.5-103.6%), respectively, compared to T1 and T2.
- Assessment of the value of the normalized APC sensitivity ratio in clinical routine practice (Exhibition Hall) - May 17, 2024 - Abstract #ISTH2024ISTH_1092;
A 28-year-old woman under COC containing EE/DRSP with family history of VTE had a nAPCsr of 5.64. Two women, aged 41 and 42, using EE/CPA and EE/DNG had a nAPCSr of 8.64 and 8.79, respectively.
- Significance of omentin-1 and visfatin in platelet activation and blood coagulation in patients with venous thromboembolism (Exhibition Hall) - May 17, 2024 - Abstract #ISTH2024ISTH_1040;
Likewise, both TXM and prothrombin F1+2 levels were higher in VTE patients (P < 0.05). By contrast, omentin-1, anticoagulant markers, such as activated protein C, and TM were depressed in VTE patients (P < 0.05).
- Determining Thrombogenicity: Using a Modified Thrombin Generation Assay to Detect the Level of Thrombotic Event Risk in Lupus Anticoagulant-Positive Patients (Exhibition Hall) - May 17, 2024 - Abstract #ISTH2024ISTH_1035;
By contrast, omentin-1, anticoagulant markers, such as activated protein C, and TM were depressed in VTE patients (P < 0.05). We compared of the two groups
- The importance of circulating activated protein C, neutrophil extracellular trap markers, and thrombin generation test in predicting thrombotic events (Exhibition Hall) - May 17, 2024 - Abstract #ISTH2024ISTH_1034;
We obtained a VTE predictive model with APC, cfDNA, calprotectin, TGT peak and lagtime, with an area under the ROC curve (AUC) of 0.93 (95% CI: 0.85-1). When we validated our model in an independent cohort of subjects, we obtained a validated AUC of 0.96 (95% CI: 0.911-1), with the model being able to correctly classify 87% of the patients and 88% of the controls.