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Journal of Medical Cases Jul 2021Antithrombin III (AT III) is a critical component of the coagulation cascade that functions primarily to inhibit activated coagulation factors IIa and Xa. AT III...
Antithrombin III (AT III) is a critical component of the coagulation cascade that functions primarily to inhibit activated coagulation factors IIa and Xa. AT III deficiency is a disorder that predisposes patients to thromboemboli. Antiphospholipid syndrome (APS) is an autoimmune disorder that predisposes patients to vascular and microvascular thrombosis, which can often be devastating and lead to multiorgan involvement. The mainstay of treatment for both conditions involves the use of lifetime vitamin K antagonists. Recent studies suggest that patients with APS refractory to warfarin therapy may benefit from the addition of aspirin, statin, or hydroxychloroquine; low weight molecular heparin; or a combination regimen. Studies have also suggested that patients with AT III deficiency refractory to warfarin therapy may see improvement with use of a novel oral anticoagulant. This case report describes the recurrent hospitalizations of a 45-year-old patient who presented with multiorgan thrombosis involving the descending aorta, deep lower extremity veins, superior mesenteric artery and artery of the brain. This led to mesenteric ischemia, limb necrosis and a subacute frontal cortex infarct. Initial anticoagulation therapy was refractory to the use of warfarin. Enoxaparin therapy was initiated, resulting in no further thrombotic events. Clinicians should consider poor gastrointestinal absorption of warfarin in patients who fail to reach therapeutic anticoagulation goals. In addition, a thorough workup for hereditary and acquired thrombophilias should be performed in patients who present with recurrent thromboemboli, as these disorders increase the risk of poor patient outcomes if left untreated.
PubMed: 34434468
DOI: 10.14740/jmc3689 -
JPMA. the Journal of the Pakistan... Dec 2020To evaluate coagulation and fibrinolytic parameters after total joint arthroplasty (TJA) and provide evidence for optimization of timing of perioperative anticoagulation...
OBJECTIVE
To evaluate coagulation and fibrinolytic parameters after total joint arthroplasty (TJA) and provide evidence for optimization of timing of perioperative anticoagulation medicine.
METHODS
The prospective study was conducted at the Jishuitan Hospital of Peking University from January to April in 2016, and comprised patients who were scheduled consecutively to undergo primary total knee arthroplasty (TKA) or total hip arthroplasty (THA). Blood samples were obtained at day 1 preoperatively and day1, day 3 postoperatively. Antigenic levels of protein C (PC), endothelial protein C receptor (EPCR), tissue factor pathway inhibitor (TFPI), antithrombin III (AT-III), plasminogen activator inhibitor 1 (PAI-1) and tissue plasminogen activator (tPA) were measured with commercially available enzyme-linked immunosorbent assay kits.
RESULTS
Postoperative levels of coagulation parameters TFPI and AT-III were increased compared to preoperative values (118.7±34.6 vs 70.0±20.5 μg/ml for AT-III, and 26.37±7.91vs 16.68±8.92 μg/l for TFPI), while postoperative levels of coagulation parameters PC and EPCR were decreased (0.88±0.30 vs 2.03±0.66 μg/ml for PC, and 100.8±31.0 vs 199.4±57.4 μg/ml for EPCR). Postoperative levels of fibrinolytic parameter tPA was increased compared to preoperative values (2.87±0.83 vs 2.03±1.03 μg/l), while its specific inhibitor PAI-1 was decreased (0.88±0.30 vs 2.03±0.66 μg/l).
CONCLUSIONS
These results demonstrated the perturbation of the coagulation and fibrinolytic system of patients undergoing TJA. Hypercoagulation and hyperfibrinolysis were observed in postoperative patients, which suggested anticoagulant therapy is effective and necessary.
Topics: Biomarkers; Blood Coagulation; Fibrinolysis; Humans; Plasminogen Activator Inhibitor 1; Prospective Studies; Tissue Plasminogen Activator
PubMed: 33475556
DOI: 10.47391/JPMA.748 -
World Journal of Orthopedics Sep 2020Total joint arthroplasty is one of the most common options for end stage osteoarthritis of major joints. However, we must take into account that thrombosis after...
BACKGROUND
Total joint arthroplasty is one of the most common options for end stage osteoarthritis of major joints. However, we must take into account that thrombosis after hip/knee arthroplasty may be related to mutations in genes encoding for blood coagulation factors and immune reactions to anticoagulants [heparin-induced thrombocytopenia (HIT)/thrombosis]. Identifying and characterizing genetic risk should help to develop diagnostic strategies or modify anticoagulant options in the search for etiological mechanisms that cause thrombophilia following major orthopedic surgery.
AIM
To evaluate the impact of patients' coagulation profiles and to study specific pharmacologic factors in the development of post-arthroplasty thrombosis.
METHODS
In 212 (51 male and 161 female) patients that underwent primary total hip arthroplasty (100) or total knee arthroplasty (112) due to osteoarthritis during a period of 1 year, platelet counts and anti-platelet factor 4 (PF4)/heparin antibodies were evaluated pre/postoperatively, and antithrombin III, methylenetetrahydrofolate reductase, factor V and prothrombin gene mutations were evaluated preoperatively. In a minimum follow-up of 3 years, 196 patients receiving either low-molecular-weight heparins (173) or fondaparinux (23) were monitored for the development of thrombocytopenia, anti-PF4/heparin antibodies, HIT, and thrombosis.
RESULTS
Of 196 patients, 32 developed thrombocytopenia (nonsignificant correlation between anticoagulant type and thrombocytopenia, = 0134.) and 18 developed anti-PF4/heparin antibodies (12/173 for low-molecular-weight heparins and 6/23 for fondaparinux; significant correlation between anticoagulant type and appearance of antibodies, = 0.005). Odds of antibody emergence: 8.2% greater in patients receiving fondaparinux than low-molecular-weight heparins. Gene mutations in factor II or V (two heterozygotes for both factor V and II) were identified in 15 of 196 patients. Abnormal low protein C and/or S levels were found in 3 of 196 (1.5%) patients, while all patients had normal levels of von Willebrand factor, lupus anticoagulant, and antithrombin III. Four patients developed HIT (insignificant correlation between thrombocytopenia and antibodies) and five developed thrombosis (two had positive antibodies and two were heterozygotes for both factor II & V mutations). Thrombosis was not significantly correlated to platelet counts or HIT. The correlation of thrombosis to antibodies, factor II, factor V was = 0.076, = 0.043, = 0.013, respectively.
CONCLUSION
Screening of coagulation profile, instead of platelet monitoring, is probably the safest way to minimize the risk of post-arthroplasty thrombosis. In addition, fondaparinux can lead to the formation of anti-PF4/heparin antibodies or HIT.
PubMed: 32999860
DOI: 10.5312/wjo.v11.i9.400 -
International Journal of Molecular... Mar 2024Antithrombin (AT) is the major plasma inhibitor of thrombin (FIIa) and activated factor X (FXa), and antithrombin deficiency (ATD) is one of the most severe...
Antithrombin (AT) is the major plasma inhibitor of thrombin (FIIa) and activated factor X (FXa), and antithrombin deficiency (ATD) is one of the most severe thrombophilic disorders. In this study, we identified nine novel AT mutations and investigated their genotype-phenotype correlations. Clinical and laboratory data from patients were collected, and the nine mutant AT proteins (p.Arg14Lys, p.Cys32Tyr, p.Arg78Gly, p.Met121Arg, p.Leu245Pro, p.Leu270Argfs*14, p.Asn450Ile, p.Gly456delins_Ala_Thr and p.Pro461Thr) were expressed in HEK293 cells; then, Western blotting, N-Glycosidase F digestion, and ELISA were used to detect wild-type and mutant AT. RT-qPCR was performed to determine the expression of AT mRNA from the transfected cells. Functional studies (AT activity in the presence and in the absence of heparin and heparin-binding studies with the surface plasmon resonance method) were carried out. Mutations were also investigated by in silico methods. Type I ATD caused by altered protein synthesis (p.Cys32Tyr, p.Leu270Argfs*14, p.Asn450Ile) or secretion disorder (p.Met121Arg, p.Leu245Pro, p.Gly456delins_Ala_Thr) was proved in six mutants, while type II heparin-binding-site ATD (p.Arg78Gly) and pleiotropic-effect ATD (p.Pro461Thr) were suggested in two mutants. Finally, the pathogenic role of p.Arg14Lys was equivocal. We provided evidence to understand the pathogenic nature of novel mutations through in vitro expression studies.
Topics: Humans; Antithrombins; HEK293 Cells; Anticoagulants; Heparin; Mutation; Antithrombin III Deficiency
PubMed: 38474138
DOI: 10.3390/ijms25052893 -
World Journal of Hepatology Nov 2020Hepatectomy with inflow occlusion results in ischemia-reperfusion injury; however, pharmacological preconditioning can prevent such injury and optimize the postoperative...
BACKGROUND
Hepatectomy with inflow occlusion results in ischemia-reperfusion injury; however, pharmacological preconditioning can prevent such injury and optimize the postoperative recovery of hepatectomized patients. The normal inflammatory response after a hepatectomy involves increased expression of metalloproteinases, which may signal pathologic hepatic tissue reformation.
AIM
To investigate the effect of desflurane preconditioning on these inflammatory indices in patients with inflow occlusion undergoing hepatectomy.
METHODS
This is a single-center, prospective, randomized controlled trial conducted at the 4 Department of Surgery of the Medical School of Aristotle University of Thessaloniki, between August 2016 and December 2017. Forty-six patients were randomized to either the desflurane treatment group for pharmacological preconditioning (by replacement of propofol with desflurane, administered 30 min before induction of ischemia) or the control group for standard intravenous propofol. The primary endpoint of expression levels of matrix metalloproteinases and their inhibitors was determined preoperatively and at 30 min posthepatic reperfusion. The secondary endpoints of neutrophil infiltration, coagulation profile, activity of antithrombin III (AT III), protein C (PC), protein S and biochemical markers of liver function were determined for 5 d postoperatively and compared between the groups.
RESULTS
The desflurane treatment group showed significantly increased levels of tissue inhibitor of metalloproteinases 1 and 2, significantly decreased levels of matrix metalloproteinases 2 and 9, decreased neutrophil infiltration, and less profound changes in the coagulation profile. During the 5-d postoperative period, all patients showed significantly decreased activity of AT III, PC and protein S ( baseline values, < 0.05). The activity of AT III and PC differed significantly between the two groups from postoperative day 1 to postoperative day 5 ( < 0.05), showing a moderate drop in activity of AT III and PC in the desflurane treatment group and a dramatic drop in the control group. Compared to the control group, the desflurane treatment group also had significantly lower international normalized ratio values on all postoperative days ( < 0.005) and lower serum glutamic oxaloacetic transaminase and serum glutamic pyruvic transaminase values on postoperative days 2 and 3 ( < 0.05). Total length of stay was significantly less in the desflurane group ( = 0.009).
CONCLUSION
Desflurane preconditioning can lessen the inflammatory response related to ischemia-reperfusion injury and may shorten length of hospitalization.
PubMed: 33312433
DOI: 10.4254/wjh.v12.i11.1098 -
In Vivo (Athens, Greece) 2023The management of refractory ascites is critical for the treatment of patients with decompensated cirrhosis. This study aimed to evaluate the feasibility and safety of... (Observational Study)
Observational Study
Changes in Coagulation and Fibrinolytic Factors in Patients With Cirrhotic Refractory Ascites Undergoing Cell-free and Concentrated Ascites Reinfusion Therapy: A Retrospective Observational Study in Japan.
BACKGROUND/AIM
The management of refractory ascites is critical for the treatment of patients with decompensated cirrhosis. This study aimed to evaluate the feasibility and safety of cell-free and concentrated ascites reinfusion therapy (CART) in patients with cirrhosis and refractory ascites, with a focus on changes in coagulation and fibrinolytic factors in ascitic fluid following CART.
PATIENTS AND METHODS
This was a retrospective cohort study including 23 patients with refractory ascites undergoing CART. Serum endotoxin activity (EA) before and after CART and the levels of coagulation and fibrinolytic factors and proinflammatory cytokines in original and processed ascitic fluid were measured. The Ascites Symptom Inventory-7 (ASI-7) scale was used for subjective symptom assessment before and after CART.
RESULTS
Body weight and waist circumference significantly decreased after CART, whereas serum EA did not significantly change after CART. Similar to the previous reports, ascitic fluid concentrations of total protein, albumin, high-density lipoprotein cholesterol, γ-globulin, and immunoglobulin G levels were significantly increased after CART; mild elevations in body temperature and interleukin 6 and tumor necrosis factor-alpha levels in ascitic fluid were also observed. Importantly, the levels of antithrombin-III, factor VII, and X, which are useful for patients with decompensated cirrhosis, were markedly increased in the reinfused fluid during CART. Finally, the total ASI-7 score was significantly lower following CART, compared with the pre-CART score.
CONCLUSION
CART is an effective and safe approach for the treatment of refractory ascites that allows the intravenous reinfusion of coagulation and fibrinolytic factors in the filtered and concentrated ascites.
Topics: Humans; Ascites; Retrospective Studies; Japan; Ascitic Fluid; Liver Cirrhosis
PubMed: 37103093
DOI: 10.21873/invivo.13199 -
MBio Jun 2022The coronavirus disease 2019, COVID-19, is a complex disease with a wide range of symptoms from asymptomatic infections to severe acute respiratory syndrome with lethal...
The coronavirus disease 2019, COVID-19, is a complex disease with a wide range of symptoms from asymptomatic infections to severe acute respiratory syndrome with lethal outcome. Individual factors such as age, sex, and comorbidities increase the risk for severe infections, but other aspects, such as genetic variations, are also likely to affect the susceptibility to SARS-CoV-2 infection and disease severity. Here, we used a human 3D lung cell model based on primary cells derived from multiple donors to identity host factors that regulate SARS-CoV-2 infection. With a transcriptomics-based approach, we found that less susceptible donors show a higher expression level of serine protease inhibitors SERPINA1, SERPINE1, and SERPINE2, identifying variation in cellular serpin levels as restricting host factors for SARS-CoV-2 infection. We pinpoint their antiviral mechanism of action to inhibition of the cellular serine protease, TMPRSS2, thereby preventing cleavage of the viral spike protein and TMPRSS2-mediated entry into the target cells. By means of single-cell RNA sequencing, we further locate the expression of the individual serpins to basal, ciliated, club, and goblet cells. Our results add to the importance of genetic variations as determinants for SARS-CoV-2 susceptibility and suggest that genetic deficiencies of cellular serpins might represent risk factors for severe COVID-19. Our study further highlights TMPRSS2 as a promising target for antiviral intervention and opens the door for the usage of locally administered serpins as a treatment against COVID-19. Identification of host factors affecting individual SARS-CoV-2 susceptibility will provide a better understanding of the large variations in disease severity and will identify potential factors that can be used, or targeted, in antiviral drug development. With the use of an advanced lung cell model established from several human donors, we identified cellular protease inhibitors, serpins, as host factors that restrict SARS-CoV-2 infection. The antiviral mechanism was found to be mediated by the inhibition of a serine protease, TMPRSS2, which results in a blockage of viral entry into target cells. Potential treatments with these serpins would not only reduce the overall viral burden in the patients, but also block the infection at an early time point, reducing the risk for the hyperactive immune response common in patients with severe COVID-19.
Topics: Antiviral Agents; Humans; Plasminogen Activator Inhibitor 1; SARS-CoV-2; Serine Endopeptidases; Serine Proteinase Inhibitors; Serpin E2; Serpins; Virus Internalization; alpha 1-Antitrypsin; COVID-19 Drug Treatment
PubMed: 35532162
DOI: 10.1128/mbio.00892-22 -
Frontiers in Medicine 2024Limited data are available on the relationship of disseminated intravascular coagulation (DIC) with mortality in patients receiving extracorporeal membrane oxygenation...
BACKGROUND
Limited 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.
METHODS
We 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.
RESULTS
Among 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%, < 0.001). Bleeding events were significantly higher in the group of patients with a DIC score of 7 or 8 than in the other group (20.8% vs. 8.4%, = 0.038). DIC score negatively correlated with AT III level ( = -0.417, < 0.001). The predictive performance of AT III for overt DIC had statistical significance with a c-static of 0.81 (95% confidence interval (CI), 0.77-0.84, < 0.001).
CONCLUSION
Overt DIC was associated with higher in-hospital mortality and a tendency to bleed in ECMO patients. Furthermore, AT III plasma levels can easily predict overt DIC in patients undergoing ECMO. These findings suggest that monitoring AT III plasma levels may be important in the management of ECMO.
PubMed: 38716413
DOI: 10.3389/fmed.2024.1335826 -
PloS One 2022Envenomation by the European adder, Vipera berus berus (Vbb), is a medical emergency. The overall in vivo haemostatic effects of pro- and anticoagulant components in Vbb...
BACKGROUND
Envenomation by the European adder, Vipera berus berus (Vbb), is a medical emergency. The overall in vivo haemostatic effects of pro- and anticoagulant components in Vbb venom, and the downstream effects of cellular injury and systemic inflammation, are unclear.
OBJECTIVES
To longitudinally describe the global coagulation status of dogs after Vbb envenomation and compare to healthy controls. A secondary aim was to investigate differences between dogs treated with and without antivenom.
METHODS
Citrated plasma was collected at presentation, 12 hours (h), 24 h, 36 h and 15 days after bite from 28 dogs envenomated by Vbb, and from 28 healthy controls at a single timepoint. Thrombin generation (initiated with and without exogenous phospholipids and tissue factor), thrombin-antithrombin (TAT)-complexes and the procoagulant activity of phosphatidylserine (PS)-expressing extracellular vesicles (EVs), expressed as PS-equivalents, were measured.
RESULTS
At presentation the envenomated dogs were hypercoagulable compared to controls, measured as increased thrombin generation, TAT-complexes and PS-equivalents. The hypercoagulability decreased gradually but compared to controls thrombin generation and PS-equivalents were still increased at day 15. The discrepancy in peak thrombin between envenomated dogs and controls was greater when the measurement was phospholipid-dependent, indicating that PS-positive EVs contribute to hypercoagulability. Lag time was shorter in non-antivenom treated dogs, compared to antivenom treated dogs <24 h after envenomation.
CONCLUSIONS
Hypercoagulability was measured in dogs up to 15 days after Vbb envenomation. Dogs treated with antivenom may be less hypercoagulable than their non-antivenom treated counterparts. Thrombin generation is a promising diagnostic and monitoring tool for Vbb envenomation.
Topics: Animals; Antithrombin III; Antivenins; Case-Control Studies; Dog Diseases; Dogs; Female; Immunologic Factors; Inflammation; Longitudinal Studies; Male; Peptide Hydrolases; Snake Bites; Thrombin; Thrombophilia; Treatment Outcome; Viper Venoms; Viperidae
PubMed: 35180240
DOI: 10.1371/journal.pone.0263238 -
Molecules (Basel, Switzerland) Jul 2022The increasing incidence of cardiovascular diseases has created an urgent need for safe and effective antithrombotic agents. In this study, we aimed to elucidate the...
The increasing incidence of cardiovascular diseases has created an urgent need for safe and effective antithrombotic agents. In this study, we aimed to elucidate the structural characteristics and antithrombotic activity of a novel polysaccharide isolated from fruiting bodies. The purified polysaccharide AAP-b2 (12.02 kDa) was composed of mannose, glucuronic acid, glucose and xylose, with a molar ratio of 89.25:30.50:4.25:1.00. Methylation and NMR analyses showed that AAP-b2 primarily consisted of →2,3)-Manp-(1→, →3)-Manp-(1→, →4)-GlcAp-(1→ and Manp-(1→. A thrombus mouse model induced by carrageenan was used in this research to evaluate its antithrombotic effect. AAP-b2 significantly inhibited platelet aggregation, reduced the black tail length and prolonged the coagulation time, including activated partial thromboplastin time (APTT), prothrombin time (PT) and thrombin time (TT), exerting a good inhibitory effect on thrombosis in mice. The antithrombotic activity of AAP-b2 was found to be related to the inhibition of platelet activation by regulation of endothelial nitric oxide synthases (eNOs), endothelin-1 (ET-1), prostacyclin (PGI2) and thromboxane B2 (TXB2), along with the enhancement of anticoagulant activity by affecting antithrombin III (AT-III) and protein C (PC) pathways.
Topics: Animals; Blood Coagulation; Carrageenan; Fibrinolytic Agents; Mice; Platelet Aggregation; Polysaccharides; Thrombosis
PubMed: 35956781
DOI: 10.3390/molecules27154831