Search

Copyright of Journal of Modern Laboratory Medicine is the property of Journal of Modern Laboratory Medicine Editorial Department and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)

Introduction: Heparin, a commonly used anticoagulant in cardiac surgery, binds to antithrombin III (ATIII) to prevent clot formation. However, heparin resistance (HR) can complicate surgical procedures, leading to increased thromboembolic risks and bleeding complications. Proper diagnosis and management of HR are essential for optimizing surgical outcomes. Methodology: Diagnosis of HR involves assessing activated clotting time (ACT) and HR assays. Management strategies were identified through a comprehensive review of the literature, including studies exploring heparin dosage adjustments, antithrombin supplementation, and alternative anticoagulants in cardiac surgery patients with HR. A thorough search of relevant studies on HR was conducted using multiple scholarly databases and relevant keywords, resulting in 59 studies that met the inclusion criteria. Discussion: HR occurs when patients do not respond adequately to heparin therapy, requiring higher doses or alternative anticoagulants. Mechanisms of HR include AT III deficiency, PF4 interference, and accelerated heparin clearance. Diagnosis involves assessing ACT and HR assays. HR in cardiac surgery can lead to thromboembolic events, increased bleeding, prolonged hospital stays, and elevated healthcare costs. Management strategies include adjusting heparin dosage, supplementing antithrombin levels, and considering alternative anticoagulants. Multidisciplinary management of HR involves collaboration among various specialities. Strategies include additional heparin doses, fresh frozen plasma (FFP) administration, and antithrombin concentrate supplementation. Emerging alternatives to heparin, such as direct thrombin inhibitors and nafamostat mesilate, are also being explored. Conclusion: Optimizing the management of HR is crucial for improving surgical outcomes and reducing complications in cardiac surgery patients. Multidisciplinary approaches and emerging anticoagulation strategies hold promise for addressing this challenge effectively. [ABSTRACT FROM AUTHOR]

Abstract Background In critically ill cases, CRRT is a renal replacement intervention. The most common reason why CRRT terminates prematurely (non-electively) is clotting in the extracorporeal circuit, more especially in the filter. Aim of work To determine the frequency of thrombotic and hemorrhage complications throughout CRRT, the role of antithrombin III level monitoring, the type of anticoagulation, and the dose and laboratory tests utilized to monitor it. Method The study was carried out on 58 children who were undergoing CRRT. The children underwent a comprehensive history-taking, assessment, CRRT prescription parameters and alterations, vascular access data, anticoagulation type, dose, and adjustment, as well as monitoring of antithrombin III levels. Furthermore, any extracorporeal circuit clotting or bleeding was documented. Results Of the 58 sessions that were examined, 25 (43.1%) resulted in filter clotting. The indication was cured in 16 cases (27.6%), 8 cases (13.8%) resulted in the patient’s mortality, and 9 cases (15.5%) had life-threatening bleeding. The remaining 33 cases (56.9%) were not terminated with filter clotting. Forty-one (70.7%) of studied sessions used unfractionated heparin as anticoagulation, 22.4% used heparin-protamine, 5.2% was not anticoagulated, and one circuit (1.7%) was anticoagulated using regional citrate. Filter clotting incidence was significantly related to activated partial thromboplastin time (a PTT) value at the end of sessions (P value = 0.000), and platelets count after 4 h of session initiation (P value = 0.048). Antithrombin III levels pre-heparin infusion less than 80 were found in patients who received higher doses of a heparin bolus dose, median dose 35 (IQR 20–35), this relation is statistically significant (P value = 0.042). Conclusion In the 58 cases that were examined, the incidence of bleeding was 32.8%; however, 19% of the cases were not severe. The incidence of filter clotting was 43.1% in the study group. a PTT value at the end of sessions, and platelets count after 4 h could be predictors of thrombotic complications during CRRT, antithrombin III deficiency before sessions is a predictor of filter clotting.

Preeclampsia (PE) is a hypertensive pregnancy syndrome associated with target organ damage and increased cardiovascular risks, necessitating antihypertensive therapy. However, approximately 40% of patients are nonresponsive to treatment, which results in worse clinical outcomes. This study aimed to compare circulating proteomic profiles and identify differentially expressed proteins among 10 responsive (R-PE), 10 nonresponsive (NR-PE) patients, and 10 healthy pregnant controls (HP). We also explored correlations between these proteins and clinical data. Plasma protein relative quantification was performed using mass spectrometry, followed by bioinformatics analyses with the UniProt database, PatternLab for Proteomics 4.0, and MetaboAnalyst software (version 6.0). Considering a fold change of 1.5, four proteins were differentially expressed between NR-PE and R-PE: one upregulated (fibronectin) and three downregulated (pregnancy-specific beta-1-glycoprotein 1, complement C4B, and complement C4A). Between NR-PE and HP, six proteins were differentially expressed: two upregulated (clusterin and plasmin heavy chain A) and four downregulated (apolipoprotein L1, heparin cofactor II, complement C4B, and haptoglobin-related protein). Three proteins were differentially expressed between R-PE and HP: one downregulated (transthyretin) and two upregulated (apolipoprotein C1 and hemoglobin subunit beta). These findings suggest a complex interplay of these proteins involved in inflammatory, immune, and metabolic processes with antihypertensive therapy responsiveness and PE pathophysiology. [ABSTRACT FROM AUTHOR]

Background: In critically ill cases, CRRT is a renal replacement intervention. The most common reason why CRRT terminates prematurely (non-electively) is clotting in the extracorporeal circuit, more especially in the filter. Aim of work: To determine the frequency of thrombotic and hemorrhage complications throughout CRRT, the role of antithrombin III level monitoring, the type of anticoagulation, and the dose and laboratory tests utilized to monitor it. Method: The study was carried out on 58 children who were undergoing CRRT. The children underwent a comprehensive history-taking, assessment, CRRT prescription parameters and alterations, vascular access data, anticoagulation type, dose, and adjustment, as well as monitoring of antithrombin III levels. Furthermore, any extracorporeal circuit clotting or bleeding was documented. Results: Of the 58 sessions that were examined, 25 (43.1%) resulted in filter clotting. The indication was cured in 16 cases (27.6%), 8 cases (13.8%) resulted in the patient's mortality, and 9 cases (15.5%) had life-threatening bleeding. The remaining 33 cases (56.9%) were not terminated with filter clotting. Forty-one (70.7%) of studied sessions used unfractionated heparin as anticoagulation, 22.4% used heparin-protamine, 5.2% was not anticoagulated, and one circuit (1.7%) was anticoagulated using regional citrate. Filter clotting incidence was significantly related to activated partial thromboplastin time (a PTT) value at the end of sessions (P value = 0.000), and platelets count after 4 h of session initiation (P value = 0.048). Antithrombin III levels pre-heparin infusion less than 80 were found in patients who received higher doses of a heparin bolus dose, median dose 35 (IQR 20–35), this relation is statistically significant (P value = 0.042). Conclusion: In the 58 cases that were examined, the incidence of bleeding was 32.8%; however, 19% of the cases were not severe. The incidence of filter clotting was 43.1% in the study group. a PTT value at the end of sessions, and platelets count after 4 h could be predictors of thrombotic complications during CRRT, antithrombin III deficiency before sessions is a predictor of filter clotting. [ABSTRACT FROM AUTHOR]

Antithrombin III (ATIII) is a potent endogenous anticoagulant that binds to heparan sulfate proteoglycans (HSPGs) on endothelial cells' surfaces. Among these HSPGs, syndecans (SDCs) are crucial as transmembrane receptors bridging extracellular ligands with intracellular signaling pathways. Specifically, syndecan-4 (SDC4) has been identified as a key receptor on endothelial cells for transmitting the signaling effects of ATIII. Meanwhile, SDCs have been implicated in facilitating the cellular internalization of SARS-CoV-2. Given the complex interactions between ATIII and SDC4, our study analyzed the impact of ATIII on the virus entry into host cells. While ATIII binds to all SDC isoforms, it shows the strongest affinity for SDC4. SDCs' heparan sulfate chains primarily influence ATIII's SDC attachment, although other parts might also play a role in ATIII's dominant affinity toward SDC4. ATIII significantly reduces SARS-CoV-2′s cellular entry into cell lines expressing SDCs, suggesting a competitive inhibition mechanism at the SDC binding sites, particularly SDC4. Conversely, the virus or its spike protein decreases the availability of SDCs on the cell surface, reducing ATIII's cellular attachment and hence contributing to a procoagulant environment characteristic of COVID-19. [ABSTRACT FROM AUTHOR]

A 58-year-old woman presented to the emergency department with progressively worsening dyspnea and dysphagia. Her symptoms had begun 22 months earlier when dyspnea on exertion had developed. She had not had an antecedent illness or prolonged period of immobilization. After symptoms had been present for 6 months, the patient saw a pulmonologist. Pulmonary function tests showed reduced diffu- sion capacity for carbon monoxide (26% of the predicted value when adjusted for hemoglobin), as well as reduced total lung capacity, vital capacity, and residual vol- ume (63%, 57°/0, and 74% of the predicted values, respectively). Computed tomo- graphic (CT) angiography of the chest showed extensive acute emboli in both lungs with evidence of right ventricular dilatation (Fig. 1). She was admitted to the hospital, where a transthoracic echocardiogram showed right ventricular dysfunction and an estimated right ventricular systolic pressure of 42 mm Hg (normal, <36 mm Hg). The N-terminal pro-B-type natriuretic peptide (NT-proBNP) level was 2522 pg per milli- liter (reference range, <300), and the troponin I level was normal. Right heart cath- eterization and advanced therapies were deferred because her condition remained hemodynamically stable, and she was discharged while receiving apixaban; her dyspnea abated substantially. The presence of lupus anticoagulant was confirmed on repeat testing performed more than 12 weeks later (after she had not taken apixaban for 1 week). Antibodies to β2-glycoprotein land anticardiolipin and factor V Leiden and prothrombin gene mutations were not identified. Levels of protein C and pro- Win S and activity of antithrombin III were normal. She received a diagnosis of antiphospholipid antibody syndrome. Warfarin therapy was offered, but apixaban was continued given her clinically stable condition. [ABSTRACT FROM AUTHOR]

Background: Phosphorylcholine has emerged as a potential adjunctive agent in cardiopulmonary bypass (CPB) circuits. Phosphorylcholine serves as a coating for the CPB circuit, potentially enhancing biocompatibility and reducing thrombotic events. However, its impact on specific patient populations and procedural outcomes remains underexplored. Materials and Methods: In this retrospective study, we analyzed data from 60 patients who underwent cardiac surgery with CPB, comprising 20 cases each of coronary artery bypass grafting (CABG), mitral valve repair, and aortic valve replacement. The patient cohort was divided into two groups—30 patients whose CPB circuits were coated with phosphorylcholine (phosphorylcholine-coated group) and 30 patients who did not receive phosphorylcholine supplementation or circuit coating. Both groups underwent surgery with identical CPB circuit designs. We assessed the absence of adverse events, safety, and efficacy parameters, including blood loss, clotting, and the structural integrity of the CPB circuit. Additionally, we measured changes in mean albumin levels (g/dL), mean platelet counts (×109/L), and antithrombin III (ATIII) levels before and after CPB. Results: The retrospective analysis revealed an absence of adverse events in both groups. In the phosphorylcholine-coated group compared to the non-phosphorylcholine-coated group, there was a notable difference in the delta change in mean albumin levels (0.87 ± 0.1 vs. 1.65 ± 0.2 g/dL, p-value 0.021), mean platelet counts (42.251 ± 0.121 vs. 54.21 ± 0.194 × 109/L, p-value 0.049), and ATIII levels (16.85 ± 0.2 vs. 31.21 ± 0.3 p-value 0.017). There was a notable reduction in the perioperative consumption of human complex units after CPB (3 vs. 12, p-value 0.019). Conclusions: Both groups, phosphorylcholine and non-phosphorylcholine, demonstrated the absence of adverse events and that the systems are safe for iatrogenic complication. Our findings suggest that the use of phosphorylcholine coating on the CPB circuit, in the absence of supplementary phosphorylcholine, in cardiac surgery is associated with favorable changes in mean albumin levels, mean platelet counts, and ATIII levels. Further research is warranted to elucidate the full extent of phosphorylcholine's impact on patient outcomes and CPB circuit performance. [ABSTRACT FROM AUTHOR]

Protamine, first isolated from salmon fish sperm and now produced through recombinant biotechnology, is an antidote that neutralizes the anticoagulant properties of heparin. Protamine function is based on the capacity to dissociate the heparin--antithrombin III (AT III) complex (an important link that promotes blood fluidification by inhibiting coagulation), forming the inactive heparin--protamine complex. Protamine has itself dose-dependent anticoagulant properties: It interferes with coagulation factors and platelet function; it stimulates fibrinolysis; it can lead to thrombocytopenia and reduction in thrombin-related platelet aggregation; it decreases platelet response to thrombin receptor agonist in a dose-dependent manner. In this review, we will focus on protamine and its interaction with heparin. Notably, protamine is able to antagonize not only unfractionated heparin (UFH) but also low molecular weight heparins to various degrees. Protamine-allergic and anaphylactoid systemic reactions may affect up to 1 in 10 people and should be prevented and treated early. [ABSTRACT FROM AUTHOR]

Objective: To evaluate Antithrombin II and Factor V Leiden mutation in stroke among young patients and its association with various socio-demographic aspects. Study Design: Cross-sectional study. Place and Duration of Study: Pak-Emirates Military Hospital, Rawalpindi Pakistan, from Jan to Dec 2020. Methodology: A total of 103 individuals, aged 18-65 years, with acute ischemic stroke were included. The diagnosis was confirmed using computed tomography/Magnetic Resonance Imaging Brain scan. Plasma AT II activity and Factor V Leiden mutation were analyzed using standard techniques. Various socio demographic features like age, gender, body mass index, smoking, deployment at High altitude (>10,000 feet), family history of stroke and hyperlipidemia were recorded and statisticaly analyzed. Results: Only two (1.9%) patients had AT II deficiency while one (0.9%) patient showed Factor V Leiden mutation. Al patients were male. Working at high altitude, family history of stroke and tobacco smoking were related with the presence of low AT II levels (p-value <0.05). Conclusion: Testing for hypercoagulable states in the seting of stroke in young may be useful if there is family history of stroke, smoking and high-altitude deployment. Investigations to search for the cause should be tailored as per individual patients. [ABSTRACT FROM AUTHOR]

The Coronavirus Disease 2019 (COVID‐19), caused by the virus named Severe Acute Respiratory Syndrome Coronavirus 2 (SARS‐CoV‐2), is a global public health problem in which atypical findings other than the usual fever and respiratory symptoms render early diagnosis and treatment difficult. Cases with atypical clinical and laboratory presentations continue to pose a challenge in the treatment and control of the disease. This case report aims to share our follow‐up and treatment experience in a patient considered to have antithrombin III (ATIII) deficiency based on activated clotting time (ACT) levels unresponsive to heparin who was admitted to intensive care unit due to COVID‐19‐induced cytokine storm associated with extreme D‐dimer elevation (>65,000 μg/L). [ABSTRACT FROM AUTHOR]

Abstract Background Thromboembolic complications are well known in the treatment of childhood acute lymphoblastic leukemia. Over the years it has not been possible to reach a consensus on a possible prophylaxis of thromboembolic events during intensive therapy. Only the administration of enoxaparin was able to achieve evidence in the literature to date. Methods In this retrospective study, 173 childhood leukemia patients were treated over 20 years with a thromboembolic prophylaxis including enoxaparin and AT III during induction therapy with L-asparaginase and cortisone. Results We here report the effectiveness of administration of enoxaparin and AT III in childhood leukemia, showing a strikingly low prevalence of deep vein thrombosis (2.9%). Especially in adolescent patients, a particularly great need for AT III was demonstrated. Conclusions We recommend thromboembolic prophylaxis with enoxaparin and AT III substitution during induction/reinduction therapy with L-asparaginase and glucocorticosteroids, especially from adolescence onwards.

Predicting the likelihood vascular events in patients with BCR/ABL1-negative myeloproliferative neoplasms (MPN) is essential for the treatment of the disease. However, effective assessment methods are lacking. Thrombin-antithrombin complex (TAT), plasmin-α2- plasmininhibitor complex (PIC), thrombomodulin (TM), and tissue plasminogen activator-inhibitor complex (t-PAIC) are the new direct indicators for coagulation and fibrinolysis. The aim of this study was to investigate the changes of these four new indicators in thrombotic and hemorrhagic events in BCR/ABL1-negative MPN. The study cohort of 74 patients with BCR/ABL negative myeloproliferative disorders included essential thrombocythemia, polycythemia vera, and primary myelofibrosis (PMF). A panel of 4 biomarkers, including TAT, PIC, TM, and t-PAIC were determined using Sysmex HISCL5000 automated analyzers, whereas fibrin/fibrinogen degradation products (FDP), D-dimer and Antithrombin III (ATIII) were analyzed using Sysmex CS5100 coagulation analyzer. A total of 24 (32.4%) patients experienced thrombotic events and hemorrhagic events occurred in 8 patients (10.8%). Compared to patients without hemorrhagic-thrombotic events, patients with thrombotic events had higher fibrinogen (FIB) level, FDP level and lower ATIII activity, while patients with hemorrhagic events had lower white blood cell count and hemoglobin level, higher FDP level (P < 0.05). Patients with a JAK2V617F mutation were more likely to experience thrombotic events (P < 0.05). In addtion, patients with thrombotic events had higher TAT, PIC, TM, and t-PAIC levels than patients without hemorrhagic-thrombotic events (P < 0.05), whereas patients with hemorrhagic events had a lower median value in TAT and TM (no statistical difference, P > 0.05). Patients with higher TAT, TM and t-PAIC were more likely to experience thrombotic events (P < 0.05), and only TAT was positively correlated with thrombotic events (Spearman r =0.287, P = 0.019). TAT, PIC, TM, and t-PAIC combined with ATIII and FDP have a certain value for predicting thrombosis in patients with BCR/ABL1-negative MPN. These 6 parameters are worth further exploration as predictive factors and prognostic markers for early thrombotic events. [ABSTRACT FROM AUTHOR]

We studied the effectiveness of Xe/O2 mixture inhalation (30% Xe and 70% O2, 20 min for 5 days) in a model of experimental thromboplastin pneumonitis. Inhalation of the studied mixture decreased the intensity of the inflammatory process in the lung tissue assessed by the temperature response of animals, changed lung weight and lung weight coefficient. At acute stage of pneumonitis, an increase in xenon consumption was recorded due to its retention in the gas exchange zone and a natural decrease in oxygen consumption due to partial alveolar/capillary block. The formation of pneumonitis was accompanied by a pronounced procoagulant shift in the regulation system of the aggregate state of blood. The Xe/O2 inhalations ensured physiologically optimal levels of prothrombin and activated partial thromboplastin time against the background of a moderate decrease in fibrinogen level throughout the experiment. At the same time, the activity of the natural anticoagulant antithrombin III increased from day 5 to day 14. [ABSTRACT FROM AUTHOR]

Background: Thromboembolic complications are well known in the treatment of childhood acute lymphoblastic leukemia. Over the years it has not been possible to reach a consensus on a possible prophylaxis of thromboembolic events during intensive therapy. Only the administration of enoxaparin was able to achieve evidence in the literature to date. Methods: In this retrospective study, 173 childhood leukemia patients were treated over 20 years with a thromboembolic prophylaxis including enoxaparin and AT III during induction therapy with L-asparaginase and cortisone. Results: We here report the effectiveness of administration of enoxaparin and AT III in childhood leukemia, showing a strikingly low prevalence of deep vein thrombosis (2.9%). Especially in adolescent patients, a particularly great need for AT III was demonstrated. Conclusions: We recommend thromboembolic prophylaxis with enoxaparin and AT III substitution during induction/reinduction therapy with L-asparaginase and glucocorticosteroids, especially from adolescence onwards. [ABSTRACT FROM AUTHOR]

BackgroundKawasaki disease (KD) is characterized as an acute febrile inflammatory disorder, which may potentially escalate into a more severe condition termed Kawasaki disease shock syndrome (KDSS). The objective of this research is to understand the clinical attributes of KDSS and to explore the predictive significance of coagulation profiles in the incidence of KDSS.MethodPatients with Kawasaki disease (KD) were prospectively enrolled and divided into the KDSS group (n = 29) and the non-KDSS group (n = 494). Multivariate logistic regression analysis was used to ascertain the relationship between coagulation profiles and KDSS. Furthermore, ROC curve analysis was conducted to evaluate the predictive value of the coagulation profile for the occurrence of KDSS.ResultAmong the KDSS patients, the median age was higher and cervical lymph node involvement was greater compared to the non-KDSS group. Additionally pericardial effusion, valve regurgitation, cardiac enlargement, coronary artery lesions (CALs), and Intravenous immunoglobulin (IVIG) resistance were significantly more frequent in the KDSS group than in non-KDSS group. Notably, Prothrombin time (PT), activated partial thromboplastin time (APTT), D-dimer, and fibrin degradation products (FDP) were significantly elevated in the KDSS group compared to the non-KDSS group. Conversely, total thrombin time (TT), fibrinogen, and antithrombin III (ATIII) activity were significantly reduced. Multivariate logistic regression analysis revealed that PT, APTT, D-dimer, and ATIII were independent risk factors for predicting KDSS occurrence. ROC curve analysis established critical values for PT, D-dimer, FDP, and ATIII as 13.45 s, 2.03 mg/L, 7.45 μg/ml, and 77.5%, respectively. Sensitivity for predicting KDSS occurrence was 76%, 79%, 83%, and 76%, while specificity was 51%, 72%, 63%, and 80%, respectively. When we performed a combined ROC curve analysis of the four indicators, we found that its predictive sensitivity was much higher. Moreover, the Delong test results showed that the AUC of the combined analysis was significantly higher than that of the individual analyses.ConclusionCharacteristic features of KDSS include older age, a greater likelihood of experiencing pericardial effusion, valve regurgitation, cardiac enlargement, CALs, and IVIG resistance. KD patients with a hypercoagulable state during the acute phase are at a higher risk of developing KDSS.

Kateryna Strubchevska,1 Antonina Rachkovska,2 Daryna Krenytska,2 Vitalii Karbovskyy,3 Marko Kozyk,1 Benjamin Secor,4 Nataliia Raksha,2 Tetiana Vovk,2 Olexii Savchuk,2 Tetyana Falalyeyeva,2 Rostyslav Kaminsky,5 Liudmyla Ostapchenko2 1Department of Internal Medicine, Corewell Health William Beaumont University Hospital, Royal Oak, MI, USA; 2Department of Internal Medicine, Taras Shevchenko National University of Kyiv, Kyiv, Ukraine; 3Department of Internal Medicine, LLS Biopharma-Plasa, Kyiv, Ukraine; 4Department of Internal Medicine, Oakland University William Beaumont School of Medicine, Auburn Hills, MI, USA; 5Department Educational-Scientific Center ”Institute of Biology and Medicine”, Taras Shevchenko National University of Kyiv, Kyiv, UkraineCorrespondence: Marko Kozyk, 3601 W 13 Mile Road, Royal Oak, MI, 48073, Tel +1-305-773-5089, Email marko.kozyk@corewellhealth.orgBackground and Objectives: Post-COVID-19 condition is thought to affect 10– 20% of people at least 3 months after a diagnosis of COVID-19 and two months of symptoms. Post-COVID-19 condition presents itself with many clinical effects with varying degrees of severity ranging from a mild cough to a life-threatening coagulopathy. Our study aimed to identify a relationship between the titers of anti-SARS-CoV-2 IgG and anticoagulation parameters: antithrombin III (ATIII), protein C (PC) and thrombomodulin (TM).Materials and Methods: Blood plasma was collected from healthy donors aged 25– 45 who had recovered from COVID-19 3– 6 months ago and their titers of anti-SARS-CoV-2 IgG and ATIII, PC, and TM were measured.Results: We found that concentrations and activities of key anticoagulation parameters (ATIII, PC, and TM) measured in donor plasma during the post-COVID-19 varied in relation to the titers of anti-SARS-CoV-2 IgG.Conclusion: While we identified a dysfunction of anticoagulation parameters in patients with post-COVID-19, we aim to explore the subpopulation antibody IgG fraction directly using in vivo and in vitro experiments with the possibility to contribute to the development of treatment options for post-COVID-19 conditions.Keywords: long-COVID, antithrombin III, thrombomodulin, protein C

Mucopolysaccharidosis type I (MPS I) is a lysosomal storage disorder caused by α-L-iduronidase deficiency. The standard treatment, enzyme replacement therapy with laronidase, has limited effectiveness in treating neurological symptoms due to poor blood–brain barrier penetration. An alternative is substrate reduction therapy using molecules, such as genistein, which crosses this barrier. This study evaluated the effectiveness of a combination of laronidase and genistein in a mouse model of MPS I. Over 12 weeks, MPS I and wild-type mice received laronidase, genistein, or both. Glycosaminoglycan (GAG) storage in visceral organs and the brain, its excretion in urine, and the serum level of the heparin cofactor II–thrombin (HCII-T) complex, along with behavior, were assessed. The combination therapy resulted in reduced GAG storage in the heart and liver, whereas genistein alone reduced the brain GAG storage. Laronidase and combination therapy decreased liver and spleen weights and significantly reduced GAG excretion in the urine. However, this therapy negated some laronidase benefits in the HCII-T levels. Importantly, the combination therapy improved the behavior of female mice with MPS I. These findings offer valuable insights for future research to optimize MPS I treatments. [ABSTRACT FROM AUTHOR]

Serine proteases are members of a large family of hydrolytic enzymes in which a particular serine residue in the active site performs an essential role as a nucleophile, which is required for their proteolytic cleavage function. The array of functions performed by serine proteases is vast and includes, among others, the following: (i) the ability to fight infections; (ii) the activation of blood coagulation or blood clot lysis systems; (iii) the activation of digestive enzymes; and (iv) reproduction. Serine protease activity is highly regulated by multiple families of protease inhibitors, known collectively as the SERine Protease INhibitor (SERPIN). The serpins use a conformational change mechanism to inhibit proteases in an irreversible way. The unusual conformational change required for serpin function provides an elegant opportunity for allosteric regulation by the binding of cofactors, of which the most well-studied is heparin. The goal of this review is to discuss some of the clinically relevant serine protease–serpin interactions that may be enhanced by heparin or other negatively charged polysaccharides. The paired serine protease–serpin in the framework of heparin that we review includes the following: thrombin–antithrombin III, plasmin–anti-plasmin, C1 esterase/kallikrein–C1 esterase inhibitor, and furin/TMPRSS2 (serine protease Transmembrane Protease 2)–alpha-1-antitrypsin, with the latter in the context of COVID-19 and prostate cancer. [ABSTRACT FROM AUTHOR]

Intrauterine growth restriction (IUGR) is defined as a fetal failure to reach the genetic potential for intrauterine growth. IUGR complicates up to 10% of pregnancies, representing a primary cause of morbidity and mortality. Hereditary thrombophilia has been detected in about 65% of pregnancies and because of the association with IUGR, preeclampsia, uteroplacental apoplexy, recurrent miscarriage and fetal intrauterine death, prenatal testing is recommended. Our study included a number of 122 patients without pre-existing pregnancy pathology (study group) who were compared with a control group that included 122 patients with normal birth weight fetuses. Patients were evaluated at about 6-7 weeks postnatally when we tried to correlate the intrauterine growth restriction with the profile of hereditary thrombophilia (determination of factor II gene mutations, factor V Leiden, MTHFR gene, PAI gene, factor XIII mutation, antithrombin III, protein C, protein S). The results of the study showed the presence of hereditary thrombophilia in 82 cases (67.2%) in the study group and in 21 cases (17.21%) in the control group. Among the genetic analyses performed we found a predominance of PAI-1 gene as well as a positive association with intrauterine growth restriction in case of concomitant presence of factor V Leiden and PAI-1 gene or MTHFR gene. [ABSTRACT FROM AUTHOR]

Background: Bleeding and thrombosis are common extracorporeal membrane oxygenation (ECMO) complications associated with increased mortality. Heparin is the most commonly used ECMO anticoagulant, employed in 94% of cases. Reduced antithrombin III (AT3) levels could decrease heparin effectiveness. Neonates have inherently lower levels of AT3 than adults, and pediatric patients on ECMO can develop AT3 deficiency. One potential approach for patients on ECMO with AT3 deficiency is exogenous AT3 supplementation. However, there is conflicting data concerning the use of AT3 for pediatric and neonatal patients on ECMO. Methods: We analyzed the Bleeding and Thrombosis during ECMO database of 514 neonatal and pediatric patients on ECMO. We constructed daily regression models to determine the association between AT3 supplementation and rates of bleeding and thrombosis. Given the physiological differences between pediatric patients and neonates, we constructed separate models for each. Results: AT3 administration was associated with increased rates of daily bleeding among pediatric (adjusted odds ratio [aOR] 1.59, p < 0.01) and neonatal (aOR 1.37, p = 0.04) patients. AT3 supplementation did not reduce the rate of thrombosis for either pediatric or neonatal patients. Conclusion: AT3 administration was associated with increased rates of daily bleeding, a hypothesized potential complication of AT3 supplementation. In addition, AT3 supplementation did not result in lower rates of thrombosis. We recommend clinicians utilize caution when considering supplementing patients on ECMO with exogenous AT3. [ABSTRACT FROM AUTHOR]

Purpose: Progestin-only pills (POPs), compared to combined, are not associated with an increased risk of venous thromboembolism, but are associated with a poor cycle control. the aim of this study was to evaluate the impact of a new POP [4 mg drospirenone (DRsP) for 24 days with a 4-day hormone-free interval] on some coagulation markers (both procoagulant and fibrinolytic) and to describe its impact on bleeding patterns. Materials and methods: this is a prospective trial, based on serum evaluation of following coagulation markers and tests: Factor (F) X, F Viii, F V, iNR, aPtt, Protein s and antithrombin iii. a 'bleeding diary' was used to categorise women as having (1) unscheduled bleeding, (2) scheduled bleeding and (3) amenorrhoea. thirty patients were followed for six 28-day intake cycles, with a follow-up at the end of the 3rd and 6th cycles. Results: there was a significant decrease of F X (p = 0.03) (-5.7% at cycle 6). No significant changes have been observed for F Vii, F V and iNR. a significant increase in aPtt (p = 0.01 at 3 cycles), Protein s (p = 0.0006 at 3 cycles) and antithrombin iii (p < 0.0001 at 3 cycles) was recorded. this non-deteriorating coagulation impact was associated with a significant and progressive reduction of days of scheduled and unscheduled bleeding in users between cycles 4 and 6 (from 1.3 ± 0.2 days at cycle 4 to 0.8 ± 0.1 days at cycle 6 and from 2.6 ± 0.4 days at cycle 4 to 0.6 ± 0.2 days at cycle 6, respectively, p < 0.0001). Conclusions: DRsP 24 + 4 use was associated with a non-deteriorating effect on coagulation markers and a significant progressive reduction of days of scheduled and unscheduled bleeding. [ABSTRACT FROM AUTHOR]

BackgroundLimited data are available on the relationship of disseminated intravascular coagulation (DIC) with mortality in patients receiving extracorporeal membrane oxygenation (ECMO). Thus, we investigated the association of DIC score and antithrombin (AT) III with clinical outcomes in patients undergoing ECMO.MethodsWe analyzed 703 patients who underwent ECMO between January 2014 and May 2022 at Samsung Medical Center. The DIC score was calculated using laboratory findings within 24 h of the ECMO initiation, and ≥ 5 was defined as overt DIC. In addition, the AT III level was measured to identify the correlation with the DIC score.ResultsAmong the study patients, 169 (24.0%) were diagnosed with overt DIC (DIC group) during early maintenance therapy. In-hospital mortality was significantly higher in the DIC group than in the non-DIC group (55.0% vs. 36.5%, p

Antithrombin III (ATIII) is a potent endogenous anticoagulant that binds to heparan sulfate proteoglycans (HSPGs) on endothelial cells’ surfaces. Among these HSPGs, syndecans (SDCs) are crucial as transmembrane receptors bridging extracellular ligands with intracellular signaling pathways. Specifically, syndecan-4 (SDC4) has been identified as a key receptor on endothelial cells for transmitting the signaling effects of ATIII. Meanwhile, SDCs have been implicated in facilitating the cellular internalization of SARS-CoV-2. Given the complex interactions between ATIII and SDC4, our study analyzed the impact of ATIII on the virus entry into host cells. While ATIII binds to all SDC isoforms, it shows the strongest affinity for SDC4. SDCs’ heparan sulfate chains primarily influence ATIII’s SDC attachment, although other parts might also play a role in ATIII’s dominant affinity toward SDC4. ATIII significantly reduces SARS-CoV-2′s cellular entry into cell lines expressing SDCs, suggesting a competitive inhibition mechanism at the SDC binding sites, particularly SDC4. Conversely, the virus or its spike protein decreases the availability of SDCs on the cell surface, reducing ATIII’s cellular attachment and hence contributing to a procoagulant environment characteristic of COVID-19.

Background: The role of natural anticoagulant deficiency in the development of arterial thrombosis (AT) is controversial. Objective: Our objectives were to assess the deficiency of natural anticoagulants, including protein S (PS), protein C (PC), antithrombin III (AT III) and their involvement in the occurrence of AT. Design: Retrospective cross-sectional study. Methods: This study was conducted in 585 patients who were examined with PS, PC, and AT III tests. The activity of PC, PS (men, women), and ATIII under 70%, 75%, 60%, and 80% was recognized as a deficiency, respectively. Peripheral blood cell and coagulation tests were performed before starting treatment. Patients with previous AT, venous thromboembolism (VTE) or anticoagulant therapy were excluded. Results: Patients without thrombosis were 222 (38%), patients with newly diagnosed VTE were 281 (48%), and patients with newly diagnosed AT were 82 (14%). The most common AT sites were in the lungs, brain, and lower extremities (31.2%, 20.8%, and 20.8%, respectively). Compared to the nonthrombosis group, the AT group had a lower PS activity (%) (82.77 ± 24.09 vs 91.31 ± 27.27), a higher fibrinogen (g/L) (4.25 ± 1.68 vs 3.74 ± 1.51), a higher D-dimer (mg/L FEU) (6.16 vs 1.95), and a higher neutrophil count (G/L) (8.57 vs 6.50) with P <.05. Compared to the VTE group, the AT group had higher hemoglobin (g/L) (135.95 ± 23.75 vs 129.02 ± 25.22) and a higher neutrophil count (G/L) (8.57 vs 7.28) (P <.05). In the AT group, the frequencies of PC, PS, and AT III deficiency were 23.1%, 28%, and 17.1%, respectively. The AT group had a higher frequency of PS deficiency than the nonthrombosis group (28% vs 17.1%, P =.035). Patients with PS deficiency had a higher risk of AT compared to those without PS deficiency (OR = 1.888, 95% CI [1.041-3.422], P =.036). Conclusion: PS deficiency may be considered a factor in increasing the risk of AT. [ABSTRACT FROM AUTHOR]

Background: Thrombosis remains a critical complication during venovenous extracorporeal membrane oxygenation (VV ECMO). The involvement of neutrophil extracellular traps (NETs) in thrombogenesis has to be discussed. The aim was to verify NETs in the form of cell‐free DNA (cfDNA) in the plasma of patients during ECMO. Methods: A fluorescent DNA‐binding dye (QuantifFluor®, Promega) was used to detect cell‐free DNA in plasma samples. cfDNA concentrations from volunteers (n = 21) and patients (n = 9) were compared and correlated with clinical/technical data before/during support, ECMO end and time of a system exchange. Results: Before ECMO, patients with a median (IQR) age of 59 (51/63) years, SOFA score of 11 (10/15), and ECMO run time of 9.0 (7.0/19.5) days presented significantly higher levels of cfDNA compared to volunteers (6.4 (5.8/7.9) ng/μL vs. 5.9 (5.4/6.3) ng/μL; p = 0.044). Within 2 days after ECMO start, cfDNA, inflammatory, and hemolysis parameters remained unchanged, while platelets decreased (p = 0.005). After ECMO removal at the end of therapy, cfDNA, inflammation, and coagulation data (except antithrombin III) remained unchanged. The renewal of a system resulted in known alterations in fibrinogen, d‐dimers, and platelets, while cfDNA remained unchanged. Conclusion: Detection of cfDNA in plasma of ECMO patients was not an indicator of acute and circuit‐induced thrombogenesis. [ABSTRACT FROM AUTHOR]

Antithrombin III is an important anticoagulant factor with anti-inflammatory properties. However, few studies have explored its anti-inflammatory actions in ATIII overexpressed transgenic animals. In this study, the dairy goats with mammary overexpression of ATIII were used to investigate their general health, milk quality and particularly their response to inflammatory challenge. The results showed that transgenic goats have a normal phenotype regarding their physiological and biochemical parameters, including whole blood cells, serum protein levels, total cholesterol, urea nitrogen, uric acid, and total bilirubin, compared to the WT. In addition, the quality of milk also improved in transgenic animals compared to the WT, as indicated by the increased milk fat and dry matter content and the reduced somatic cell numbers. Under the stimulation of an LPS injection, the transgenic goats had elevated contents of IGA, IGM and superoxide dismutase SOD, and had reduced proinflammatory cytokine release, including IL-6, TNF-α and IFN-β. A 16S rDNA sequencing analysis also showed that the transgenic animals had a similar compositions of gut microbiota to the WT goats under the stimulation of LPS injections. Mammary gland ATIII overexpression in dairy goats is a safe process, and it did not jeopardize the general health of the transgenic animals; moreover, the compositions of their gut microbiota also improved with the milk quality. The LPS stimulation study suggests that the increased ATIII expression may directly or indirectly suppress the inflammatory response to increase the resistance of transgenic animals to pathogen invasion. This will be explored in future studies. [ABSTRACT FROM AUTHOR]

Introduction: Hereditary antithrombin-III deficiency can significantly increase the risk for thrombosis, which is common in limb deep vein and pulmonary cases. However, thrombotic microangiopathy (TMA) caused by hereditary antithrombin deficiency is rare. Case Presentation: We reported the case of a 32-year-old Chinese female patient with TMA with renal injury caused by decreased antithrombin-III activity due to a new mutation (chr1-173884049 c.50A>G) in SERPINC1, which encodes antithrombin-III. In this case, the patient had no history of relevant drug use, diabetes, or monoclonal plasma cells in the bone marrow puncture. Consequently, TMA of the kidney was considered secondary to hereditary antithrombin-III deficiency. Gene detection was the only clue that led us to suspect that TMA was caused by hereditary antithrombin deficiency. Conclusion: Our findings indicated that for patients with repeated findings of antithrombin-III activity less than 50%, the possibility of antithrombin-III deficiency and complete gene detection must be considered immediately after excluding the use of anticoagulants and lack of availability to facilitate early detection, diagnosis, and intervention. [ABSTRACT FROM AUTHOR]

We examined the temporal changes of the CSF proteome in patients with herpes simplex encephalitis (HSE) during the course of the disease, in relation to anti-N-methyl-D-aspartate receptor (NMDAR) serostatus, corticosteroid treatment, brain MRI and neurocognitive performance. Patients were retrospectively included from a previous prospective trial with a pre-specified CSF sampling protocol. Mass spectrometry data of the CSF proteome were processed using pathway analysis. We included 48 patients (110 CSF samples). Samples were grouped based on time of collection relative to hospital admission – T1: ≤ 9 d, T2: 13–28 d, T3: ≥ 68 d. At T1, a strong multi-pathway response was seen including acute phase response, antimicrobial pattern recognition, glycolysis and gluconeogenesis. At T2, most pathways activated at T1 were no longer significantly different from T3. After correction for multiplicity and considering the effect size threshold, 6 proteins were significantly less abundant in anti-NMDAR seropositive patients compared to seronegative: procathepsin H, heparin cofactor 2, complement factor I, protein AMBP, apolipoprotein A1 and polymeric immunoglobulin receptor. No significant differences in individual protein levels were found in relation to corticosteroid treatment, size of brain MRI lesion or neurocognitive performance. We show a temporal change in the CSF proteome in HSE patients during the course of the disease. This study provides insight into quantitative and qualitative aspects of the dynamic pathophysiology and pathway activation patterns in HSE and prompts for future studies on the role of apolipoprotein A1 in HSE, which has previously been associated with NMDAR encephalitis. [ABSTRACT FROM AUTHOR]

Β-thalassemia is the severe form of genetic illnesses which decreases the hemoglobin synthesis. One of the major complications in thalassemic syndromes, including β -thalassemia major and intermedia is thromboembolic events. In addition, thromboembolic events are more common in non -transfusion -dependent thalassemia than those in well -transfusion -dependent β -thalassemia. A combination of hypercoagulable states including, abnormalities in red blood cells, and platelet, antithrombin III, protein C, and protein S, and splenectomy are involved in thrombotic events, but thromboembolic events can be prevented and treated in these patients via blood transfusion, hydroxyurea, anticoagulants, and aspirin. Moreover, recent studies have demonstrated the involvement of the brain lesion in β -thalassemia patients. The involvement of vascular events of brain in patients with β -thalassemia intermedia is 29 -83%, but the rate of asymptomatic brain lesions in the healthy people is 0 -11%. In addition, neurological complications which have been attributed to various factors are chronic hypoxia, iron overload, bone marrow expansion, and desferrioxamine neurotoxicity. This review evaluated thromboembolic events and neurological lesions in patients with β -thalassemia and its probable curative therapy. [ABSTRACT FROM AUTHOR]

Background: We present the case study of a 28-year-old pregnant woman with antithrombin deficiency who was treated with low-molecular-weight heparin (LMWH). Methods: Due to severe homozygous type II antithrombin heparin binding site (HBS) deficiency, the thrombin generation (TG) was monitored in this woman via the Thrombin Generation Assay (TGA). We used Siemens diagnostic kits Berichrom® Antithrombin III (IIa) and INNOVANCE® Antithrombin (Xa) to determine antithrombin activity. We used a chromogenic method for determination of factor Xa (FXa) inhibition. Results: There were no thrombotic complications during the whole pregnancy of the observed woman. Antithrombin was administered before and after delivery, which was significantly reflected in the decrease in thrombin generation. Conclusions: Consistent monitoring of thrombin generation with LMWH anticoagulant therapy administration during pregnancy together with antithrombin administration before and after delivery can improve the overall condition of pregnant women and the quality of their care. [ABSTRACT FROM AUTHOR]

Newborns are the most vulnerable patients for thrombosis development among all children, with critically ill and premature infants being in the highest risk group. The upward trend in the rate of neonatal thrombosis could be attributed to progress in the treatment of severe neonatal conditions and the increased survival in premature babies. There are physiological differences in the hemostatic system between neonates and adults. Neonates differ in concentrations and rate of synthesis of most coagulation factors, turnover rates, the ability to regulate thrombin and plasmin, and in greater variability compared to adults. Natural inhibitors of coagulation (protein C, protein S, antithrombin, heparin cofactor II) and vitamin K-dependent coagulation factors (factors II, VII, IX, X) are low, but factor VIII and von Willebrand factor are elevated. Newborns have decreased fibrinolytic activity. In the healthy neonate, the balance is maintained but appears more easily converted into thrombosis. Neonatal hemostasis has less buffer capacity, and almost 95% of thrombosis is provoked. Different triggering risk factors are responsible for thrombosis in neonates, but the most important risk factors for thrombosis are central catheters, fluid fluctuations, liver dysfunction, and septic and inflammatory conditions. Low-molecular-weight heparins are the agents of choice for anticoagulation. [ABSTRACT FROM AUTHOR]

Background: As an emerging standard of care for portal vein cavernous transformation (PVCT), Meso-Rex bypass (MRB) has been complicated and variated. The study aim was to propose a new classification of PVCT to guide MRB operations. Methods: Demographic data, the extent of extrahepatic PVCT, surgical methods for visceral side revascularization, intraoperative blood loss, operating time, changes in visceral venous pressure before and after MRB, postoperative complications and the condition of bypass vessels after MRB were extracted retrospectively from the medical records of 19 patients. Results: The median age of the patients (13 males and 6 females) was 32.5 years, while two patients were underage. Causes of PVCT can be summarized as follows: thrombophilia such as dysfunction of antithrombin III or proteins C; secondary to abdominal surgeries; secondary to abdominal infection or traumatic intestinal obstruction, and unknown causes. Intraoperatively, the median operation time was 9.5 h (7–13 h), and the intraoperative blood loss was 300 mL (100-1,600 mL). Ten cases used autologous blood vessels while 10 used allogeneic blood vessels. The vascular anastomosis was divided into the following types according to the site and approach: Type (T) 1-PV pedicel type, T2-confluence type, T3-major visceral vascular type; and T4-collateral visceral vascular type. Furthermore, the visceral venous pressure before and after MRB dropped significantly from 36 cmH2O (28–44) to 24.5 cmH2O (15–31) (P < 0.01). Postoperatively, one patient had delayed wound healing, two developed biochemical pancreatic fistulae, one experienced lymphatic leakage, the former caused by heat damage of the pancreatic tissues, the latter by cutting lymphatic vessels in the mesentery or removing the local lymph nodes during the process of separating the superior mesenteric vein, and one was re-operated on for an intervening intestinal fistulae. Postoperative enhanced CT scans revealed a significant improvement in abdominal varix in the patients with patent bypass, and at the 1-year postoperative follow-up, enhanced CT scans of six patients showed that the long axis of the spleen was reduced by ≥ 2 cm. Conclusions: MRB can effectively reduce visceral venous pressure in patients with PVCT. It is feasible to determine the PVCT type according to the extent of involvement and to choose individualized visceral side revascularization performances. [ABSTRACT FROM AUTHOR]