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Heparin mimetics as potential intervention for COVID-19 and their bio-manufacturing

Synthetic and Systems Biotechnology 2023年第1期8卷 11-19页

作者： Lan Jiang Tianji Zhang Hongzhong Lu Saijuan Li Kangjie Lv Alex Tuffour Lixin Zhang Kan Ding Jin-Ping Li Hongmei Li Xueting Liu Department of Cardiothoracic Surgery Children’s Hospital of Nanjing Medical UniversityNanjing210093China State Key Laboratory of Bioreactor Engineering East China University of Science and TechnologyShanghai200237China Division of Chemistry and Analytical Science Key Laboratory of Chemical Metrology and Applications on Nutrition and Health for State Market RegulationNational Institute of MetrologyBeijing100029China State Key Laboratory of Microbial Metabolism and School of Life Sciences and Biotechnology Shanghai Jiao Tong UniversityShanghai200240China Glycochemistry&Glycobiology Lab Key Laboratory of Receptor ResearchShanghai Institute of Materia MedicaChinese Academy of SciencesShanghai201203China International Research Center for Soft Matter Beijing University of Chemical TechnologyBeijing100029China Department of Medical Biochemistry and Microbiology University of UppsalaUppsalaSweden

The COVID-19 pandemic has caused severe health problems worldwide and unprecedented decimation of the global economy.Moreover,after more than 2 years,many populations are still under pressure of infection.Thus,a broader perspective in developing antiviral strategies is still of great importance.Inspired by the observed multiple benefits of Heparin in the treatment of thrombosis,the potential of low molecular weight Heparin(LMWH)for the treatment of COVID-19 have been explored.Clinical applications found that LMWH decreased the level of inflammatory cytokines in COVID-19 patients,accordingly reducing lethality.Furthermore,several in vitro studies have demonstrated the important roles of heparan sulfate in SARS-CoV-2 infection and the inhibitory effects of Heparin and Heparin mimetics in viral infection.These clinical observations and designed studies argue for the potential to develop Heparin mimetics as anti-SARS-CoV-2 drug candidates.In this review,we summarize the properties of Heparin as an anticoagulant and the pharmaceutical possibilities for the treatment of virus infection,focusing on the perspectives of developing Heparin mimetics via chemical synthesis,chemoenzymatic synthesis,and bioengineered production by microbial cell factories.The ultimate goal is to pave the eminent need for exploring novel compounds to treat coronavirus infection-caused diseases.

关键词： Heparin Biosynthesis Biological activities Bio-production

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Anti-infection effects of Heparin on SARS-CoV-2 in a diabetic mouse model

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Zoological Research 2023年第6期44卷 1003-1014页

作者： Zhongyun Zhang Ning Zhang Xuancheng Lu Min Zhou Xiaoxiang Yan Weiqiong Gu Jingru Yang Qin Zhang Cheng Zhang Yuhuan Gong Mingjun Jia Xiaoyu Zhang Peng Ning Mei Liu Xiaoyan Li Xiaomeng Shi Wenjun Liu George FGao Guang Ning Jiqiu Wang Yuhai Bi Department of Endocrinology and Metabolism Shanghai Institute of Endocrine and Metabolic DiseasesRuijin HospitalShanghai Jiao Tong University School of MedicineShanghai 200025China Shanghai National Clinical Research Center for Metabolic Diseases Key Laboratory for Endocrine and Metabolic Diseases of the National Health Commission of the PR ChinaShanghai National Center for Translational MedicineShanghai 200025China CAS Key Laboratory of Pathogen Microbiology and Immunology Institute of MicrobiologyCenter for Influenza Research and Early-warning(CASCIRE)CAS-TWAS Center of Excellence for Emerging Infectious Diseases(CEEID)Chinese Academy of SciencesBeijing 100101China Laboratory Animal Center Chinese Center for Disease Control and Prevention(China CDC)Beijing 102206China Department of Respiratory and Critical Care Medicine Institute of Respiratory DiseasesRuijin HospitalShanghai Jiao Tong University School of MedicineShanghai 200025China Department of Cardiology Institute of Cardiovascular DiseasesRuijin HospitalShanghai Jiao Tong University School of MedicineShanghai 200025China School of Laboratory Medicine and Life Sciences Wenzhou Medical UniversityWenzhouZhejiang 325000China University of Chinese Academy of Sciences Beijing 100049China

Severe acute respiratory syndrome coronavirus 2(SARSCo V-2)infection can result in more severe syndromes and poorer outcomes in patients with diabetes and obesity.However,the precise mechanisms responsible for the combined impact of coronavirus disease 2019(COVID-19)and diabetes have not yet been elucidated,and effective treatment options for SARS-Co V-2-infected diabetic patients remain limited.To investigate the disease pathogenesis,K18-h ACE2 transgenic(h ACE2^(Tg))mice with a leptin receptor deficiency(h ACE2-Lepr^(-/-))and high-fat diet(h ACE2-HFD)background were generated.The two mouse models were intranasally infected with a 5×10^(5) median tissue culture infectious dose(TCID_(50))of SARSCo V-2,with serum and lung tissue samples collected at 3days post-infection.The h ACE2-Lepr^(-/-)mice were then administered a combination of low-molecular-weight Heparin(LMWH)(1 mg/kg or 5 mg/kg)and insulin via subcutaneous injection prior to intranasal infection with1×10^(4) TCID_(50)of SARS-Co V-2.Daily drug administration continued until the euthanasia of the mice.Analyses of viral RNA loads,histopathological changes in lung tissue,and inflammation factors were conducted.Results demonstrated similar SARS-Co V-2 susceptibility in h ACE2^(Tg)mice under both lean(chow diet)and obese(HFD)conditions.However,compared to the h ACE2-Lepr^(+/+)mice,h ACE2-Lepr^(-/-)mice exhibited more severe lung injury,enhanced expression of inflammatory cytokines and hypoxia-inducible factor-1α(HIF-1α),and increased apoptosis.Moreover,combined LMWH and insulin treatment effectively reduced disease progression and severity,attenuated lung pathological changes,and mitigated inflammatory responses.In conclusion,preexisting diabetes can lead to more severe lung damage upon SARS-Co V-2 infection,and LMWH may be a valuable therapeutic approach for managing COVID-19patients with diabetes.

关键词： SARS-CoV-2 Diabetes Mouse model Heparin Antiviral therapy

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Effect of uninterrupted dabigatran or rivaroxaban on achieving ideal activated clotting time to Heparin response during catheter ablation in patients with atrial fibrillation

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Journal of Geriatric Cardiology 2022年第8期19卷 565-574页

作者： Qian XIN Chuang ZHANG Yu-Jia WANG Jian LI Tao CHEN Shi-Xing LI Wei WANG Yu YANG Wen-Juan SONG Jin ZHOU Xiang-Min SHI Department of Cardiology the Sixth Medical CentreChinese PLA General HospitalBeijingChina Department of Health Service the Eighth Medical CentreChinese PLA General HospitalBeijingChina

BACKGROUND Uninterrupted use of oral anticoagulants before atrial fibrillation(AF)ablation can reduce the incidence of perioperative thromboembolic events.However,the effect of new oral anticoagulants on activated clotting time(ACT)in respo-nse to Heparin during AF ablation in Chinese populations remains unknown.The aim of the present retrospective study was to investigate the value of ACTs in response to intraoperative Heparin administration in patients using dabigatran or rivaroxaban.METHODS From January 2018 to December 2021,a total of 173 patients undergoing AF ablation were included in the study,in which 101 patients were treated with dabigatran,72 patients were treated with rivaroxaban.The intraoperative ACT values were examined in both groups.The incidence of periprocedural complications was evaluated.RESULTS Initial Heparin dosage(88±19 U/kg vs.78±27 U/kg,PHeparin dosage(137±41 U/kg vs.106±52 U/kg,P<0.05)during the ablation procedure were higher in the dabigatran group than those in the rivaroxaban group.Mean ACT(280±36 s vs.265±30 s,P<0.05),and the percentage of ACTs within the therapeutic range(250-350 s)(74%±26%vs.60%±29%,P<0.05)were significantly lower in the dabigatran group than those in the rivaroxaban group,particularly in male pati-ents.Furthermore,the average time of achieving the target ACT(250-350 s)was also found longer in the dabigatran group(P<0.05)as compared with the rivaroxaban group.No significant difference was found in the incidence of periprocedural complica-tions between the two groups.CONCLUSIONS The anticoagulant effect of uninterrupted rivaroxaban therapy appears to be more stable and efficient than dabigatran administration during catheter ablation in patients with AF.

关键词： patients Heparin dosage

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A new Heparin fragment decreases liver ischemia-reperfusion injury

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Hepatobiliary & Pancreatic Diseases International 2022年第2期21卷 190-192页

作者： Enio R Vasques Estela RR Figueira Joel A Rocha-Filho Cinthia Lanchotte Jorge LS Ximenes Helena B Nader Ivarne LS Tersariol Marcelo A Lima Tiago Rodrigues JoséEM Cunha Eleazar Chaib Luiz AC D’Albuquerque Flávio HF Galvão Laboratorio de Investigaçao Medica 37 Departamento de GastroenterologiaHospital das Clinicas HCFMUSPFaculdade de MedicinaUniversidade de São PauloSão Paulo 01246-903Brazil Departamento de Gastroenterologia Hospital das Clinicas HCFMUSPFaculdade de MedicinaUniversidade de São PauloSão PauloBrazil Disciplina de Anestesiologia Hospital das Clinicas HCFMUSPFaculdade de MedicinaUniversidade de São PauloSão PauloBrazil Departamento de Bioquimica Universidade Federal de São PauloSão PauloBrazil Universidade Federal do ABC Santo AndreSão PauloBrazil Serviço de Transplante de Figado e Orgaos do Aparelho Digestivo Departamento de GastroenterologiaHospital das Clinicas HCFMUSPFaculdade de MedicinaUniversidade de São PauloSão PauloBrazil

To the Editor:Ischemia-reperfusion injury following surgery and transplantation can lead to irreversible multiorgan failure.Intracellular calcium overload is associated to cellular death during ischemiareperfusion.A recently discovered Heparin fragment (HF),trisulfated disaccharide (TD),that acts on sodium-calcium exchanger(NCX) decreasing intracellular Ca^(2+),showed effectiveness on protecting hepatocytes from ischemia-reperfusion injury [1].

关键词： irreversible Heparin injury

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Heparin/Growth Factors‑Immobilized Aligned Electrospun Nanofibers Promote Nerve Regeneration in Polycaprolactone/Gelatin‑Based Nerve Guidance Conduits

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Advanced Fiber Materials 2023年第2期5卷 554-573页

作者： Yasuhiro Ikegami Muhammad Shafiq Shinichi Aishima Hiroyuki Ijima Department of Chemical Engineering Faculty of EngineeringGraduate SchoolKyushu University744 MotookaNishi‑KuFukuoka 819‑0395Japan Department of Biotechnology Faculty of Science and TechnologyUniversity of Central Punjab(UCP)Lahore 54000Pakistan Department of Pathology and Microbiology Faculty of MedicineSaga UniversityNabeshima 5‑1‑1Saga 849‑8501Japan

Injuries to the nervous system account for the widespread morbidity,mortality,and discomfort worldwide.Artificial nerve guidance conduits(NGCs)offer a promising platform for nerve reconstruction,however,they require extracellular matrix(ECM)-like features to better mimic the in vivo microenvironment.Consequently,this research was aimed to fabricate Heparin/growth factors(GFs)-immobilized artificial NGCs.Heparin was covalently immobilized onto aligned electrospun polycapro-lactone/gelatin(PCL/Gel)nanofibers.Thereafter,basic fibroblast growth factor(bFGF)and nerve growth factor(NGF)were preferentially immobilized on Heparinized nanofibers;the immobilization efficiency of GFs was found to be 50%with respect to(w.r.t.)their initial loaded amounts.The in vivo implantation of NGCs in a sciatic nerve defect model revealed the successful retention(~10%w.r.t the initial loaded amount)and bioactivity of NGF for up to 5 days.The permeability of bovine serum albumin(BSA)from nanofibrous membranes was further assessed and found to be comparable with the commercialized cel-lulose acetate membranes.The bioactivity of NGCs was assessed in a sciatic nerve defect model in rats for short-term(1 week)and long-term(1-month).The NGCs displayed good structural stability and biocompatibility in vivo.The in vivo evaluation revealed the accumulation of host cells into the transplanted NGCs.Taken together;these Heparin/GFs-immobilized artificial NGCs may have broad implications for nerve regeneration and related tissue engineering disciplines.

关键词： Heparin Growth factor-immobilized scaffolds Aligned nanofibers Core/shell nanofibers Nerve tissue engineering Scaffolds Co-axial electrospinning

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Heparin is an effective treatment for preventing liver failure after hepatectomy

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World Journal of Gastroenterology 2024年第22期30卷 2881-2892页

作者： Zhi-Ying Xu Min Peng Ming-Ming Fan Qi-Fei Zou Yi-Ran Li Dong Jiang Hepatic Surgery IV Shanghai Eastern Hepatobiliary Surgery HospitalThe Third Affiliated Hospital of Naval Medical UniversityShanghai 200433China Ultrasound Diagnosis PLA Naval Medical CenterShanghai 200437China Department of Ultrasound Eastern Hepatobiliary Surgery HospitalThe Third Affiliated Hospital of Naval Medical UniversityShanghai 200433China

BACKGROUND Posthepatectomy liver failure(PHLF)is one of the most important causes of death following liver resection.Heparin,an established anticoagulant,can protect liver function through a number of mechanisms,and thus,prevent liver failure.AIM To look at the safety and efficacy of Heparin in preventing hepatic dysfunction after hepatectomy.METHODS The data was extracted from Multiparameter Intelligent Monitoring in Intensive Care III(MIMIC-III)v1.4 pinpointed patients who had undergone hepatectomy for liver cancer,subdividing them into two cohorts:Those who were injected with Heparin and those who were not.The statistical evaluations used were unpaired ttests,Mann-Whitney U tests,chi-square tests,and Fisher’s exact tests to assess the effect of Heparin administration on PHLF,duration of intensive care unit(ICU)stay,need for mechanical ventilation,use of continuous renal replacement therapy(CRRT),incidence of hypoxemia,development of acute kidney injury,and ICU mortality.Logistic regression was utilized to analyze the factors related to PHLF,with propensity score matching(PSM)aiming to balance the preoperative disparities between the two groups.RESULTS In this study,1388 patients who underwent liver cancer hepatectomy were analyzed.PSM yielded 213 matched pairs from the Heparin-treated and control groups.Initial univariate analyses indicated that Heparin potentially reduces the risk of PHLF in both matched and unmatched samples.Further analysis in the matched cohorts confirmed a significant association,with Heparin reducing the risk of PHLF(odds ratio:0.518;95%confidence interval:0.295-0.910;P=0.022).Additionally,Heparin treatment correlated with improved short-term postoperative outcomes such as reduced ICU stay durations,diminished requirements for respiratory support and CRRT,and lower incidences of hypoxemia and ICU mortality.CONCLUSION Liver failure is an important hazard following hepatic surgery.During ICU care Heparin administration has been proved to decrease the occurrence of hepatectomy induced liver

关键词： Liver resection Posthepatectomy liver failure Prophylactic treatment Heparin Prognosis of hepatectomy

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Effectiveness and safety of therapeutic plasma exchange to modify the functionality of Heparin-induced thrombocytopenia antibodies and correct profound thrombocytopenia:A case report and literature review

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Journal of Intensive Medicine 2023年第4期3卷 373-375页

作者： Audrey Graser Anne Bauters Jean-Luc Auffray Caroline Vayne François Provot Merce Jourdain Laurent Robriquet Department of Intensive Care Medicine CHU LilleLille F-59000France Service d'Hémostase-Transfusion Institut d'HématologieCentre de Biologie Pathologie GénétiqueBoulevard du Professeur Jules LeclercqCentre Hospitalier Universitaire de LilleLille 59037France Service de Cardiologie Institut Coeur PoumonBoulevard du Professeur Jules LeclercqCentre Hospitalier Universitaire de LilleLille 59037France Service d'Hématologie-Hémostase Centre Hospitalier Universitaire de ToursUniversitéde ToursTours EA4245 T2IFrance Pôle de Néphrologie Hôpital Albert CalmetteBoulevard du Professeur Jules LeclercqCentre Hospitalier Universitaire de LilleLille 59037France Department of Intensive Care Medicine Univ LilleInsermCHU LilleLille F-59000France

Introduction Heparin-induced thrombocytopenia(HIT)is a rare but life-threatening complication of Heparin therapy.Specific IgG antibodies recognize Heparin-modified platelet factor 4(PF4/H IgG)and activate the platelet... 详细信息

关键词： Heparin antibodies thrombocytopenia

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Prenatal administration of Heparin-binding epidermal growth factor-like growth factor in an experimental model of necrotizing enterocolitis decreased both incidence and severity of the disease

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World Journal of Pediatric Surgery 2022年第1期5卷 18-24页

作者： Marla Ashley Sacks Yomara Stephanie Mendez Faraz A Khan Robert Propst Craig W Zuppan Christopher G Wilson Andrei Radulescu Division of Pediatric Surgery Department of SurgeryLoma Linda University Children's HospitalLoma LindaCaliforniaUSA Department of Pathology Loma Linda University Children's HospitalLoma LindaCaliforniaUSA Department of Neonatology Loma Linda University Children's HospitalLoma LindaCaliforniaUSA

background Necrotizing enterocolitis(NEC)is the leading gastrointestinal cause of death in premature infants and causes long-term disabilities.Previously,enteral Heparin-binding epidermal growth factor-like growth factor(HB-EGF)administered after birth demonstrated decreased incidence and severity of NEC in a neonatal animal model of NEC.We investigated the potential prophylactic strategy of preventing NEC using prenatally administered HB-EGF.Methods An HB-EGF(800μg/kg/dose)dose was injected into pregnant rats via tail vein or intraperitoneal route 2 hours prior to delivery.After cesarean section(C-section)at 21 days’gestation,the rat pups were subjected to the NEC protocol by inducing stressors:hypoxia,hypothermia,hypertonic feeds,and orogastric gavage of lipopolysaccharide(2 mg/kg).Postnatally,pups were monitored for 96 hours and assessed for the development of clinical and postmortem histological NEC.results The experimental NEC incidence in untreated,stressed rat pups was 66%.Compared with untreated pups,the maternal administration of HB-EGF correlated with a significant NEC incidence and severity decrease in rat pups.The strongest decrease was seen when HB-EGF was administered via the intraperitoneal route 2 hours prior to C-section(66%vs 31%,*p<0.05).Prenatal HB-EGF administration significantly increased pups’survival after NEC protocol exposure,with the greatest benefit observed in the group that received HB-EGF intraperitoneally 2 hours before delivery.Conclusions Prenatal administration of HB-EGF decreases the incidence and severity of NEC,preserves gut barrier function and increases survival.This may represent a novel prophylactic clinical strategy for NEC offered to mothers at risk of delivering a premature infant.

关键词： severity Heparin incidence

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Unfractionated Heparin attenuates endothelial barrier dysfunction via the phosphatidylinositol-3 kinase/serine/threonine kinase/nuclear factor kappa-B pathway

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Chinese Medical Journal 2020年第15期133卷 1815-1823页

作者： Sheng-Tian Mu Jie Tang Jian-Qi Ma Yu Zhong Han-Zhe Liu Xiao-Chun Ma Zhen Zheng Department of Intensive Care Unit Cancer Hospital of China Medical UniversityLiaoning Cancer Hospital and InstituteShenyangLiaoning 110042China Department of Intensive Care Unit The First Affiliated Hospital of China Medical UniversityShenyangLiaoning 110001China

Background::Vascular endothelial dysfunction is considered a key pathophysiologic process for the development of acute lung injury.In this study,we aimed at investigating the effects of unfractionated Heparin(UFH)on the lipopolysaccharide(LPS)-induced changes of vascular endothelial-cadherin(VE-cadherin)and the potential underlying mechanisms.Methods::Male C57BL/6 J mice were randomized into three groups:vehicle,LPS,and LPS+UFH groups.Intraperitoneal injection of 30 mg/kg LPS was used to induce sepsis.Mice in the LPS+UFH group received subcutaneous injection of 8 U UFH 0.5 h before LPS injection.The lung tissue of the mice was collected for assessing lung injury by measuring the lung wet/dry(W/D)weight ratio and observing histological changes.Human pulmonary microvascular endothelial cells(HPMECs)were cultured and used to analyze the effects of UFH on LPS-or tumor necrosis factor-alpha(TNF-α)-induced vascular hyperpermeability,membrane expression of VE-cadherin,p120-catenin,and phosphorylated myosin light chain(p-MLC),and F-actin remodeling,and on the LPS-induced activation of the phosphatidylinositol-3 kinase(PI3K)/serine/threonine kinase(Akt)/nuclear factor kappa-B(NF-κB)signaling pathway.Results::In vivo,UFH pretreatment significantly attenuated LPS-induced pulmonary histopathological changes(neutrophil infiltration and erythrocyte effusion,alveolus pulmonis collapse,and thicker septum),decreased the lung W/D,and increased protein concentration(LPS vs.LPS+UFH:0.57±0.04 vs.0.32±0.04 mg/mL,P=0.0092),total cell count(LPS vs.LPS+UFH:9.57±1.23 vs.3.65±0.78×105/mL,P=0.0155),polymorphonuclear neutrophil percentage(LPS vs.LPS+UFH:88.05%±2.88%vs.22.20%±3.92%,P=0.0002),and TNF-α(460.33±23.48 vs.189.33±14.19 pg/mL,P=0.0006)in the bronchoalveolar lavage fluid.In vitro,UFH pre-treatment prevented the LPS-induced decrease in the membrane expression of VE-cadherin(LPS vs.LPS+UFH:0.368±0.044 vs.0.716±0.064,P=0.0114)and p120-catenin(LPS vs.LPS+UFH:0.208±0.018 vs.0.924±0.092,P=0.0016),and the LPS-induced increase in the express

关键词： Acute lung injury Cadherin Capillary permeability Heparin

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Heparin-induced thrombocytopenia occurring early after living donor liver transplantation:a case report

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Emergency and Critical Care Medicine 2023年第4期3卷 198-202页

作者： Naoya Iwasaki Motohiro Sekino Takanobu Hara Akihiko Soyama Masaaki Hidaka Yusuke Kasai Miki Suzumura Hiroshi Araki Rintaro Yano Sojiro Matsumoto Taiga Ichinomiya Ushio Higashijima Susumu Eguchi Tetsuya Har Department of Anesthesiology and Intensive Care Medicine Nagasaki University Graduate School of Biomedical SciencesNagasakiJapan Department of Surgery Nagasaki University Graduate School of Biomedical SciencesNagasakiJapan

Background:Thrombocytopenia commonly occurs early after liver transplantation.Heparin,usually administered as anticoagulant ther-apy for thrombosis,a common complication after liver transplantation,may cause Heparin-induced thrombocytopenia.Heparin-induced thrombocytopenia is a rare but life-threatening complication,and its diagnosis after liver transplantation is challenging.Case presentation:We report a case of Heparin-induced thrombocytopenia after living donor liver transplantation with a good out-come because of early diagnosis and discontinuation of Heparin.After liver transplantation,the platelet count usually reaches a nadir on postoperative days 3–5 and gradually recovers.In contrast,Heparin-induced thrombocytopenia typically occurs 5–10 days after Heparin administration;therefore,if Heparin is started intraoperatively,then thrombocytopenia will occur on postoperative days 5–10.Conclusion:Monitoring the trend and timing of thrombocytopenia and detailed examination for thrombosis may help confirm the diag-nosis of Heparin-induced thrombocytopenia in the early stage after liver transplantation.

关键词： Case report Heparin Heparin-induced thrombocytopenia Liver transplantation Thrombocytopenia Thrombosis

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