Microsurgical breast reconstruction and primary hypercoagulable disorders.

BACKGROUND: Primary hypercoagulable disorders pose a significant challenge to microsurgeons and have traditionally been regarded as a relative contraindication to free tissue transfer. Since free flaps offer numerous advantages in breast reconstruction, there is an effort to expand the population to whom these operations can be safely offered. The purpose of this study is to describe our chemoprophylaxis regimen in cases of primary hypercoagulability, as well as to compare flap outcomes and complications between women with and without hypercoagulability. PATIENTS AND METHODS: A single institution retrospective review identified 15 patients (25 flaps) with known primary hypercoagulability who underwent microsurgical breast reconstruction from 2010 through 2020. There were 785 patients (1268 flaps) without primary hypercoagulability who underwent microsurgical breast reconstruction, including 40 patients (73 flaps) with a history of venous thromboembolism (VTE), evaluated for comparison. Patient characteristics, thromboprophylaxis regimen, and surgical outcomes were collected. In carrying out this cohort study, we have adhered to Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) guidelines. RESULTS: Fifteen patients with primary hypercoagulability were identified, including heterozygous factor V Leiden mutation (n = 12), protein S deficiency (n = 1), prothrombin mutation (n = 1), and primary antiphospholipid syndrome (n = 1). Thirteen of these (87%) were discharged with an extended LMWH course. There was no postoperative VTE or mortality in this cohort, and no significant difference in hematoma or transfusion compared with the control group (p = .31, p = .87, respectively). The flap loss rate was 4% in the hypercoagulable group compared with 0.92% in the control group (p = .15). The salvage for arterial or venous compromise in the hypercoagulable group was poor (0% vs. 52%, p = .3). CONCLUSION: Microsurgical breast reconstruction in women with primary hypercoagulability disorders is feasible with acceptable risk of flap loss but poor salvage potential. Postoperative thromboprophylaxis with extended prophylactic LMWH in this population appears to be a safe regimen.

Successful microvascular surgery in patients with thrombophilia in head and neck surgery: a case series.

BACKGROUND: In this case series, a perioperative anticoagulation protocol for microvascular head and neck surgery in patients with thrombophilia is presented. Microvascular free-flap surgery is a standard procedure in head and neck surgery with high success rates. Nevertheless, flap loss-which is most often caused by thrombosis-can occur and has far-reaching consequences, such as functional impairment, prolonged hospitalization, and increased costs. The risk of flap loss owing to thrombosis is significantly increased in patients with thrombophilia. Therefore, perioperative anticoagulation is mandatory. To date, no perioperative anticoagulation protocol exists for these high-risk patients. CASE PRESENTATION: We present three exemplary male Caucasian patients aged 53-57 years with free flap loss owing to an underlying, hidden thrombophilia. CONCLUSION: We present a modified anticoagulation protocol for microvascular surgery in these high-risk patients, enabling successful microsurgical reconstruction.

D-Dimer Trends Predict Recurrent Stroke in Patients with Cancer-Related Hypercoagulability.

INTRODUCTION: In patients with cancer-associated hypercoagulability (CAH)-related stroke, D-dimer trends after anticoagulant therapy may offer a biomarker of treatment efficacy. The purpose of this study was to clarify the association between D-dimer trends and recurrent stroke after anticoagulant therapy in patients with CAH-related stroke. METHODS: We performed retrospective cohort study of consecutive patients with CAH-related stroke at two stroke centers from 2011 to 2020. The ratio of posttreatment to pretreatment D-dimer levels (post/pre ratio) was used as an indicator of D-dimer trends after anticoagulant therapy. Fine-Gray models were used to evaluate the association between post/pre ratio and recurrent stroke. RESULTS: Among 360 acute ischemic stroke patients with active cancer, 73 patients with CAH-related stroke were included in this study. Recurrent stroke occurred in 13 patients (18%) during a median follow-up time of 28 days (interquartile range, 11-65 days). Multivariate analysis revealed that high post/pre ratio was independently associated with recurrent stroke (per 0.1 increase: hazard ratio 2.20, 95% confidence interval 1.61-3.01, p = 0.012). CONCLUSION: D-dimer levels after anticoagulant therapy were associated with recurrent stroke in CAH-related stroke patients. Patients with neutral trends in high D-dimer levels after anticoagulant therapy were at high risk of recurrent stroke.

Idiopathic left-sided ovarian vein thrombosis in a post-menopausal woman.

Ovarian vein thrombosis (OVT) is a rare thromboembolic condition largely involving the right ovarian vein. Risk factors include pregnancy/ peripartum period, oestrogen therapy, recent surgery or hospitalisation, malignancy, pelvic inflammatory diseases, and thrombophilia; OVT without risk factors is considered idiopathic. We present a rare case of idiopathic left-sided OVT in a post-menopausal woman in her 60s with insignificant past medical history and no identifiable risk factors. She presented with isolated left -lower -quadrant abdominal pain ultimately found to have OVT on computed tomography (CT) scan and confirmed with magnetic resonance imaging (MRI). The patient was initially treated with low-molecular-weight heparin and then transitioned to apixaban. She remained symptom-free at 3-month follow-up. Five previous cases of idiopathic left-sided OVT have been reported to-date, but this is the first case in a postmenopausal woman that has not been associated with hypercoagulable risk factors nor further thromboembolic complications.

Prescribing DOACs with specific patient populations in mind.

What prescribing considerations should be top of mind when obesity, renal disease, cancer, or thrombophilia are at play?

Cuyun Recipe ameliorates pregnancy loss by regulating macrophage polarization and hypercoagulable state during the peri-implantation period in an ovarian hyperstimulation mouse model.

BACKGROUND: The Chinese herbal prescription Cuyun Recipe (CYR) has been widely used to treat clinical infertility and has shown good efficacy. Animal experiments have shown that CYR can promote implantation in mice, however, the exact mechanism underlying the implantation has not been elucidated. PURPOSE: To investigate the effect and mechanism of CYR on regulating macrophage polarization and hypercoagulability during the peri-implantation period in mice with ovarian hyperstimulation. METHODS: An ovarian hyperstimulation mouse model was developed, followed by treatment with CYR. Mice were sacrificed on day (D)4.5, D6, or D8 of gestation. The number of implantation sites, the pathological changes of the uterus and ovaries were assessed. The polarization of monocytes/macrophages in the spleen and endometrium, the expression and localization of cytokines were further detected. Furthermore, analyses of hypercoagulable state of the blood were also performed. RESULTS: Treatment with CYR increased the average number of implantation sites, promoted angiogenesis in endometrial, and regulated monocytes/macrophages and the cytokine levels. Moreover, CYR downregulated the overexpression of D-dimer and fgl2 after ovarian hyperstimulation. CONCLUSION: CYR facilitates embryo implantation by alleviating ovarian hyperstimulation, promoting endometrial decidualization and angiogenesis, regulating macrophage polarization, and reversing the hypercoagulable state of the blood.

Risk-Stratified Anticoagulation Protocol Increases Success of Lower Extremity Free Tissue Transfer in the Setting of Thrombophilia.

BACKGROUND: Optimal perioperative thromboprophylaxis is crucial to avoid flap thrombosis and achieve high rates of microsurgical success. At the authors' institution, implementation of a risk-stratified anticoagulation (AC) protocol preliminarily showed a reduction in postoperative thrombotic events and flap loss. The authors present an updated analysis of surgical outcomes using risk-stratified AC in thrombophilic patients who underwent free tissue transfer (FTT) reconstruction for nontraumatic lower extremity (LE) wounds. METHODS: The authors retrospectively reviewed patients who underwent FTT to an LE from 2012 to 2021. Their risk-stratification AC protocol was implemented in July of 2015. Low-risk and moderate-risk patients received subcutaneous heparin. High-risk patients received heparin infusion titrated to a goal partial thromboplastin time of 50 to 70 seconds. Before July of 2015, nonstratified patients were treated with either subcutaneous heparin or low-dose heparin infusion (500 U/hour). Patients were divided into two cohorts (nonstratified and risk-stratified) based on date of FTT reconstruction. Primary outcomes included rates of postoperative complications, flap salvage, and flap success. RESULTS: Two hundred nineteen hypercoagulable patients who underwent FTT to an LE were treated with nonstratified ( n = 26) or risk-stratified ( n = 193) thromboprophylaxis. The overall flap success rate was 96.8% ( n = 212). Flap loss was lower among risk-stratified patients (1.6% versus 15.4%; P = 0.004), which paralleled a significant reduction in postoperative thrombotic events (2.6% versus 15.4%; P = 0.013). Flap salvage was accomplished more often in the risk-stratified cohort (80% versus 0%; P = 0.048). Intraoperative anastomotic revision (OR, 6.10; P = 0.035) and nonrisk stratification (OR, 9.50; P = 0.006) were independently associated with flap failure. CONCLUSIONS: Hypercoagulability can significantly affect microsurgical outcomes. Implementation of a risk-stratified AC protocol can significantly improve flap outcomes. CLINICAL QUESTION/LEVEL OF EVIDENCE: Therapeutic, III.

Enhanced thrombin generation detected with ST-Genesia analyzer in patients with newly diagnosed multiple myeloma.

The issue of how to identify newly diagnosed multiple myeloma (NDMM) patients requiring thromboprophylaxis remains unsolved. Several changes in thrombin generation (TG)-derived parameters have been described in multiple myeloma (MM) patients recently. Assessment of prothrombotic risk with a fully automated TG analyzer could reduce interlaboratory variability. Our objective was to determine whether ST-Genesia® could reveal a hypercoagulable state in NDMM compared to healthy controls. We conducted a multicenter observational study of NDMM requiring initial treatment to compare TG parameters obtained with ST-Genesia® analyzer and ST-ThromboScreen® reagent with a control group. Clinical data were obtained from medical records and blood samples were collected before initial anti-myeloma therapy. A thrombophilia panel was performed in all patients. Compared to age- and sex-matched controls (n = 83), NDMM patients (n = 83) had significantly higher peak height, higher velocity index, shorter time-to-peak and lower percentage of endogenous thrombin potential (ETP) inhibition after adding thrombomodulin (TM) (ETP%inh). NDMM on prophylactic low molecular weight heparin (LMWH) showed reduced both peak height and velocity index compared to NDMM who had not yet started VTE prophylaxis, similar to that of controls. Moreover, partial correction of ETP%inh was observed in MM patients on LMWH. The presence of a thrombophilia did not modify the TG phenotype. Untreated NDMM patients showed an enhanced TG, regardless of their thrombophilia status. They generate a higher peak of thrombin, take less time to produce it, and exhibit resistance to TM inhibition. Our findings suggest that standard prophylactic dose of LMWH may reduce TG at levels of healthy controls.

Hormone replacement therapy in women with history of thrombosis or a thrombophilia.

Findings from the Women's Health Initiative (WHI) randomised placebo-controlled trial (RCT) were published at the beginning of this century. They suggested that hormone replacement therapy (HRT) use increased the risk of cardiovascular disease and venous thromboembolism including pulmonary embolism and deep vein thrombosis The findings led to a decline in HRT prescriptions and negative publicity about the use of HRT for women with significant menopausal symptoms. Subsequent studies have shown that the risk of thrombosis with HRT relates to whether estrogen is combined with a progestogen and the route of administration of estrogen. In healthy women with no background medical problems, transdermal hormone replacement is not associated with an increased risk of thrombosis. However, much less is known about the safety of various HRT preparations in women with a high background risk of thrombosis. These cases can often be challenging for clinicians with uncertainties around testing for thrombophilia, use of anticoagulation and striking a balance between the risks and benefits of prescribing HRT. This article will review the mechanism of thrombosis with differing types of HRT and present the evidence from the relevant trials. The article will also present the evidence that specifically relates to women with a personal history of thrombosis or thrombophilia (heritable and acquired) to enable clinicians to better individualise the risk assessment for each woman requesting HRT and understand the role of thrombophilia screening or concomitant anticoagulation in such situations.

Perioperative Hypercoagulability in Free Flap Reconstructions Performed for Intracranial Tumors.

OBJECTIVE(S): Patients with intracranial tumors have a higher risk of thromboembolic events. This risk increases at the time of surgical intervention. We have noted an anecdotal increase in perioperative flap thrombosis in patients undergoing free tissue transfer for intracranial tumor resection. This study aims to formally evaluate this risk. METHODS: A multi-institutional retrospective chart review was performed of patients who underwent free tissue transfer for scalp/cranial reconstruction. Perioperative thrombosis and free flap outcomes were evaluated. RESULTS: The 209 patients who underwent 246 free tissue transfers were included in the study. The 28 free flap scalp reconstructions were associated with intracranial tumors, 19 were performed following composite cranial resections with associated dural resection/reconstruction, and 199 were performed in the absence of intracranial tumors (control group). There was a significantly higher incidence of perioperative flap thrombosis in the intracranial tumor group (11/28, 39%) when compared to controls (38/199, 19%) (p = 0.0287). This was not seen when scalp tumors extended to the dura alone (4/19, 21%, p = 0.83). Therapeutic anticoagulation used for perioperative thrombosis (defined as intraoperative or in the immediate postoperative phase up to 5 days) was associated with a lower risk of flap failure, although this was not statistically significant (p = 0.148). Flap survival rates were equivalent between flaps performed for intracranial pathology (93.3%) and controls (95%). CONCLUSION: There is an increase in perioperative flap thrombosis in patients with intracranial tumors undergoing free tissue scalp reconstruction. Anticoagulation appears to mitigate this risk. LEVEL OF EVIDENCE: This recommendation is based on level 3 evidence (retrospective case-control studies, systematic review of retrospective studies, and case reports) Laryngoscope, 133:1103-1109, 2023.

Hypercoagulability in Cushing's syndrome: incidence, pathogenesis and need for thromboprophylaxis protocols.

Cushing's syndrome (CS) is associated with a hypercoagulable state resulting in an increased risk on venous thromboembolism (VTE). In patients with untreated active CS VTE incidence is up to 18-fold higher compared to the general population, whereas after pituitary and adrenal surgery a postoperative VTE risk between 2.6 and 5.6% has been reported. Interestingly, after surgery the VTE risk is not only increased in the first week but also during several months postoperatively. The hypercoagulable state in CS is thought to be caused, at least in part, by an imbalance between activity of pro- and anticoagulant pathways. However, changes in activated partial thromboplastin time and plasma concentrations of pro-and anticoagulant factors are not observed in every CS patient. Only retrospective studies have shown that thromboprophylaxis lowers VTE risk in CS. Future prospective studies should asses the optimal timing, duration and type of thromboprophylaxis in CS to improve VTE-related morbidity and mortality.

Antithrombotic treatment of retinal vein occlusion: a position statement from the Italian Society on Thrombosis and Haemostasis (SISET).

Retinal vein occlusion (RVO) represents a common cause of visual impairment and blindness. RVO may be associated with both local (e.g., hyperopia, glaucoma) and systemic (e.g., hypertension, diabetes, smoking, obesity, and dyslipidaemia) risk factors. The association with thrombophilia remains controversial. Data on the use of antithrombotic therapy for RVO are poor and inconsistent with most of the information being derived from observational studies. Here we provide a position statement from the Italian Society on Thrombosis and Haemostasis (SISET) to guide the clinical and therapeutic management of patients with RVO based on the available evidence and expert opinion.

Modulation of Cellular NAD+ Attenuates Cancer-Associated Hypercoagulability and Thrombosis via the Inhibition of Tissue Factor and Formation of Neutrophil Extracellular Traps.

Cancer-associated thrombosis is the second-leading cause of mortality in patients with cancer and presents a poor prognosis, with a lack of effective treatment strategies. NAD(P)H quinone oxidoreductase 1 (NQO1) increases the cellular nicotinamide adenine dinucleotide (NAD+) levels by accelerating the oxidation of NADH to NAD+, thus playing important roles in cellular homeostasis, energy metabolism, and inflammatory responses. Using a murine orthotopic 4T1 breast cancer model, in which multiple thrombi are generated in the lungs at the late stage of cancer development, we investigated the effects of regulating the cellular NAD+ levels on cancer-associated thrombosis. In this study, we show that dunnione (a strong substrate of NQO1) attenuates the prothrombotic state and lung thrombosis in tumor-bearing mice by inhibiting the expression of tissue factor and formation of neutrophil extracellular traps (NETs). Dunnione increases the cellular NAD+ levels in lung tissues of tumor-bearing mice to restore the declining sirtuin 1 (SIRT1) activity, thus deacetylating nuclear factor-kappa B (NF-κB) and preventing the overexpression of tissue factor in bronchial epithelial and vascular endothelial cells. In addition, we demonstrated that dunnione abolishes the ability of neutrophils to generate NETs by suppressing histone acetylation and NADPH oxidase (NOX) activity. Overall, our results reveal that the regulation of cellular NAD+ levels by pharmacological agents may inhibit pulmonary embolism in tumor-bearing mice, which may potentially be used as a viable therapeutic approach for the treatment of cancer-associated thrombosis.

Coagulation profiles and viscoelastic testing in multisystem inflammatory syndrome in children.

OBJECTIVE: To characterize viscoelastic testing profiles of children with multisystem inflammatory syndrome in children (MIS-C). METHODS: This single-center retrospective review included 30 patients diagnosed with MIS-C from March 1 to September 1, 2020. Thromboelastography (TEG) with platelet mapping was performed in 19 (63%) patients and compared to age- and sex-matched controls prior to cardiac surgery. Relationships between TEG parameters and inflammatory markers were assessed using correlation. RESULTS: Patients with MIS-C had abnormal TEG results compared to controls, including decreased kinetic (K) time (1.1 vs. 1.7 minutes, p < .01), increased alpha angle (75.0° vs. 65.7°, p < .01), increased maximum amplitude (70.8 vs. 58.3 mm, p < .01), and decreased lysis in 30 minutes (Ly30) (1.1% vs. 3.7%, p = .03); consistent with increased clot formation rate and strength, and reduced fibrinolysis. TEG maximum amplitude was moderately correlated with erythrocyte sedimentation rate (ESR) (r = 0.60, p = .02), initial platelet count (r = 0.67, p < .01), and peak platelet count (r = 0.51, p = .03). TEG alpha angle was moderately correlated with peak platelet count (r = 0.54, p = .02). Seventeen (57%) patients received aspirin (ASA) and anticoagulation, five (17%) received only ASA, and three (10%) received only anticoagulation. No patients had a symptomatic thrombotic event. Six (20%) patients had a bleeding event, none of which was major. CONCLUSIONS: Patients with MIS-C had evidence of hypercoagulability on TEG. Increased ESR and platelets were associated with higher clot strength. Patients were prophylactically treated with ASA or anticoagulation with no symptomatic thrombosis or major bleeding. Further multicenter study is required to characterize the rate of thrombosis and optimal thromboprophylaxis algorithm in this patient population.

IgG4-related pachymeningitis and mastoiditis, associated with cerebral venous thrombosis: A case report.

IgG4-related disease (IgG4-RD) is a multisystem fibroinflammatory condition; this can be a challenging diagnosis that requires clinico-pathologic correlation. We report a young woman, presenting with cranial nerve palsy. The work-up revealed pachymeningitis, cerebral venous thrombosis (CVT), and a destructive lesion in the mastoid. We diagnosed IgG4-RD through mastoidectomy. Thus, a biopsy of asymptomatic, infrequently affected organs, like the mastoid, can meet all histopathological criteria. In neuro-meningeal presentations, CVT may be secondary to the local inflammatory environment of pachymeningitis. Since our patient had a deep vein thrombosis one year prior, we discuss a possible higher risk of thrombosis in IgG4-RD patients.

COVID-19 and acute limb ischemia: a systematic review.

INTRODUCTION: The main goal of this systematic review was to analyze the outcomes of acute limb ischemia (ALI) in patients suffering from the novel Coronavirus: COVID-19 (SARS-CoV-2). EVIDENCE ACQUISITION: A systematic review on Medline and Embase was conducted up to May 15, 2021. All papers were sorted by abstract and full text by two independent authors. Systematic reviews, commentaries, and studies that did not distinguish status of COVID-19 infection were excluded from review. Patient demographics were recorded along with modality of treatment (endovascular and/or surgical). We analyzed 30-day outcomes, including mortality. Primary outcome was to evaluate clinical characteristic of ALI in patients affected by SARS-CoV-2 in term of location of ischemia, treatment options and 30-day outcomes. EVINDENCE SYNTHESIS: We selected 36 articles with a total of 194 patients. Most patients were male (80%) with a median age of 60 years old. The treatment most used was thromboembolectomy (31% of all surgical interventions). A total of 32 patients (19%) were not submitted to revascularization due to critical status. The rate of technical success was low (68%), and mortality rate was high (35%). CONCLUSIONS: This review confirms that SARS-CoV-2 is associated with a high risk of ALI. Further studies are needed to investigate the association and elucidate potential mechanisms, which may include a hypercoagulable state and hyperactivation of the immune response. Furthermore, management of ALI is not standardized and depends on patient condition and extension of the thrombosed segment. ALI in COVID-19 patients is associated with high risk of failure of revascularization and perioperative mortality.

COVID-19 and aortic disease: a practical systematic review of the literature on management and outcomes.

INTRODUCTION: Since the outbreak of the 2019 coronavirus (COVID-19), vascular specialists have faced dramatic changes in clinical and surgical practice. Although COVID-19 pulmonary signs and symptoms were the most pertinent problems initially, in the long term, cardiovascular complications became the most fearsome, with poor outcomes in terms of morbidity and mortality. Algorithms and decision-making procedures have been modified, not only to treat new clinical findings in COVID-19 positive patients, but also to avoid complications related to pulmonary and systemic infections. Additionally, COVID-19-negative patients experienced challenging management, due to hospital crowding, the risk of nosocomial COVID-19 transmission, and pandemic emergencies. In this context, aortic interventions were subject to several difficulties. First, in COVID-19-positive patients, there was the onset of new pathological scenarios including thrombotic manifestations and the subsequent complications. Second, in both COVID-19-negative and positive patients, there was a need to deliver optimal treatment with acceptable perioperative risks, forcing a rethinking of decision-making especially in terms of indications for treatments. The aim of this systematic review is to present evidence published on COVID-19 and aortic-related issues, highlighting some challenging aspects regarding management, treatment and outcomes. EVIDENCE ACQUISITION: Data search was performed on PubMed, Scopus and Web of Science, using as time range "January 1st, 2000 - May 1st, 2021." Only articles in English language were included. Key words used for the query were "Aorta" AND "COVID-19" OR "SARS-CoV-2." Furthermore, the NCBI database of "SARS-CoV-2 Resources" was interrogated to find further relevant studies. EVIDENCE SYNTHESIS: The search retrieved 416 papers; among these, 46 studies were eligible and reviewed in depth. The published literature suggests the existence of a hypercoagulable state in patients with COVID-19 disease occurring via direct and indirect mechanisms. COVID-19 infection seems to promote a prothrombotic status that aggravates vascular disease. Regardless of clinical laboratory or status, active COVID-19 infection is considered a risk factor for poor vascular surgery outcomes. Specifically, it is associated with a fourfold increased risk of death and a threefold increased risk of major adverse events. Prognosis of patients hospitalized with COVID-19 disease is often determined by the extent of pulmonary disease, although vascular complications also greatly affect outcomes. Nevertheless, although COVID­19 is highly morbid, in high­risk operations good outcomes can still be achieved even in elderly patients with COVID­19. CONCLUSIONS: In the case of aortic disease during active COVID-19 infection, poor outcomes are associated with COVID-19 vascular and non-vascular complications, while for COVID-19-negative patients not much changed in terms of outcomes, despite the difficulties in management. Endovascular repair, when possible, minimized the impact of treatment, reducing the risk of COVID-related postoperative complications or acquired infection in negative patients.

Triptolide dose-dependently improves LPS-induced alveolar hypercoagulation and fibrinolysis inhibition through NF-κB inactivation in ARDS mice.

BACKGROUND: Alveolar hypercoagulation and fibrinolysis inhibition were associated with the refractory hypoxemia and the high mortality in patient with acute respiratory distress syndrome (ARDS), and NF-κB pathway was confirmed to contribute to the process. Triptolide (TP) significantly inhibited NF-κB pathway and thus depressed accessive inflammatory response in ARDS. We speculate that TP could improve alveolar hypercoagulation and fibrinolytic inhibition in LPS-induced ARDS via NF-κB inactivation. PURPOSE: The aim of this experiment was to explore the efficacy and potential mechanism of TP on alveolar hypercoagulation and fibrinolysis inhibition in LPS-induced ARDS in mice. METHODS: 50 µl of LPS (5 mg/ml) was inhalationally given to C57BL/6 mice to set up ARDS model. Male mice were randomly accepted with LPS, LPS + TP (1 µg/kg, 10 µg/kg, 50 µg/kg respectively), or with NEMO Binding domain peptide (NBD), an inhibitor of NF-κB. TP (1 µg/kg, 10 µg/kg, 50 µg/kg) were intraperitoneally injected or 10 µg/50 µl of NBD solution were inhaled 30 min before LPS inhalation. A same volume of normal saline (NS) substituted for TP in mice in control. The endpoint of experiment was at 8 hours after LPS stimulation. Pulmonary tissues were taken for hematoxylin-eosin (HE) staining, wet / dry ratio and for lung injury scores (LIS). Tissue factor (TF) and plasminogen activator inhibitor (PAI)-1 in lung tissue were detected by Western-blotting and by quantitative Real-time PCR(qPCR) respectively. Concentrations of TF, PAI-1, thrombin-antithrombin complex (TAT), procollagen peptide type Ⅲ (PⅢP) and activated protein C (APC) in bronchoalveolar lavage fluid (BALF) were measured by ELISA. NF-κB activation and p65-DNA binding activity in pulmonary tissue were simultaneously determined. RESULTS: LPS stimulation resulted in pulmonary edema, neutrophils infiltration, obvious alveolar collapse, interstitial congestion, with high LIS, which were all dose-dependently ameliorated by Triptolide. LPS also dramatically promoted the expressions of TF and PAI-1 either in mRNA or in protein in lung tissue, and significantly stimulated the secretions of TF, PAI-1, TAT, PⅢP but inhibited APC production in BALF, which were all reversed by triptolide treatment in dose-dependent manner. TP dose-dependently inhibited the activation of NF-κB pathway induced by LPS, indicated by the changes of phosphorylations of p65 (p-p65), p-IKKα/ß and p-IκBα, and weakened p65-DNA binding activity. TP and NBD had same efficacies either on alveolar hypercoagulation and fibrinolysis inhibition or on NF-κB signalling pathway in ARDS mice. CONCLUSIONS: TP dose-dependently improves alveolar hypercoagulation and fibrinolysis inhibition in ARDS mice through inhibiting NF-κB signaling pathway. Our data demonstrate that TP is expected to be an effective selection in ARDS.

Heparin beyond anti-coagulation.

Heparin has served as a mainstream anticoagulant for over eight decades. Clinically heparin-derived compounds significantly contribute to prevention and treatment of thrombotic events complicated in numerous medical conditions such as venous thromboembolism, coronary artery disease and extracorporeal circulation processes. Moreover in recent years, various off-labeled efficacious potentials of heparin beyond anti-coagulation are dramatically emerging, and increasingly investigated in clinical studies. Herein this article presents a comprehensive update on the expanded applications of heparin agents, covering the pregnant clinic, respiratory inflammation, renal disease, sepsis, pancreatitis, among others. It aims to maximize the beneficial profile of a pharmaceutical product through medical re-purposing development, exemplified by heparin, to address the unmet clinical needs of severe illness including coronavirus disease 2019 (COVID-19).