Fibrin degradation product D-dimer induces the synthesis and release of biologically active IL-1β, IL-6 and plasminogen activator inhibitors from monocytes in vitro

Summary Disseminated intravascular coagulation, characterized by circulating fibrin(ogen) degradation products (FDP), is associated with both acute and chronic inflammatory conditions. Since the association of FDP with monocytes could influence the release of cytokines and other regulatory proteins with significant clinical ramifications, we have studied cytokine synthesis and release following the interaction of D-dimer (DD), a terminal degradation product of fibrin, with human monocytes in vitro.
Adherent peripheral blood monocytes were incubated with purified DD for 24 and 48 h and secreted or cell-associated IL-1β and IL-6 antigen levels and activity determined. DD (50 μg/ml) boosted the secretion of IL-1β antigen from median control levels of 659 pg/ml to 2704 pg/ml and that of IL-6 antigen from 806 pg/ml to > 3000 pg/ml at 48 h ( P <0.05). Similar increases in extracellular biologically active IL-1 and IL-6 were observed. Although DD increased cell associated IL-1 β antigen levels from median values of 188 to 1600 pg/106 cells and IL-6 antigen from 660 to 2215 pg/106 cells ( P < 0.05). cell-associated IL-1 functional activity decreased from control levels of 98 inhibitor units ml to 65 units/ml for cells exposed to DD. Secreted plasminogen activator inhibitor (PAI) bioactivity and PAI type 2 antigen levels were significantly increased following exposure of monocytes to DD. This may explain the decreased cell associated IL-1 activity observed in our study as PAI are known to inhibit biologically active membrane bound IL-1.
Our finding that DD enhances monocyte release of biologically active cytokines suggests the presence of positive feedback pathways for fibrinogen synthesis by hepatocytes. Furthermore, the association of monocytes with DD may potentiate localized coagulation processes by subsequent alterations in pericellular proteolysis.     

High D-dimer level is associated with increased 15-d and 3 months mortality through a more central localization of pulmonary emboli and serious comorbidity

High D-dimer levels are predictors of death in patients with pulmonary embolism (PE), as are more proximally located, larger emboli. The direct link between these three has not yet been described. A cohort of 674 consecutive patients with confirmed PE was studied. Patients were followed up for 3 months. D-dimer levels were measured only in patients with an unlikely clinical probability ( n  = 262). The odds ratio (OR) for death of all variables was calculated. Multivariate analysis was performed to identify independent risk factors for mortality. The best predictive D-dimer cut-off point for mortality was a concentration >3000 ng/ml FEU (OR 7·29). High D-dimer levels were correlated with active malignancy and age over 65 years, both being indicators of 3-month mortality. High D-dimer levels were also correlated with centrally located pulmonary emboli and 15-d mortality. The combination of high D-dimer levels and central emboli increased early mortality risk by 2·2. High D-dimer levels in patients with an unlikely clinical probability were associated with fatal outcome after PE. Centrally located pulmonary emboli were associated with higher D-dimer levels and worse 15-d mortality. Active malignancy, being an inpatient at time of diagnosis and age over 65 years were associated with higher D-dimer levels and worse 3-month survival.     

Wells Score to Predict Pulmonary Embolism in Patients with Coronavirus Disease 2019

BackgroundThe association between coronavirus disease 2019 (COVID-19) and hypercoagulability has been extensively described, and pulmonary embolism is a recognized complication of COVID-19. Currently, the need for computed tomography pulmonary angiogram (CTPA) relies on the Wells score and serum D-dimer levels. However, because COVID-19 patients have a different thrombotic and inflammatory milieu, the usefulness of the Wells score deserves further exploration for this patient population. We aimed to explore the ability of the Wells score to predict pulmonary embolism in patients with COVID-19.MethodsIn this retrospective study, patients found to have a CTPA and a COVID-19 diagnosis during the same admission were selected for analysis. Age and sex, CTPA results, and associated D-dimer levels were entered in a database. The Wells score sensitivity and specificity were calculated at different values, and the area under the curve of the receiver operating characteristic curve measured.ResultsOf 459 patients with COVID-19, 64 had a CTPA and 12 (19%) had evidence of pulmonary embolism. Previous or current evidence of deep vein thrombosis, a Wells score above 4 points, and serum D-dimer levels 5 times above age-adjusted upper normal values were associated with pulmonary embolism. However, only 33% of patients with pulmonary embolism had a Wells score of 4 points or higher. The area under the curve of the receiver operating characteristic showed non-discriminating values (0.54)ConclusionsAlthough a Wells score of 4 or more points predicted pulmonary embolism in our cohort, the outcome can be present even with lower scores.     

Association of clinical and laboratory variables with in-hospital incidence of deep vein thrombosis in patients after acute ischemic stroke: A retrospective study

Deep vein thrombosis (DVT) is a serious complication in patients with acute ischemic stroke (AIS). Early prediction of DVT could enable physicians to perform a proper prevention strategy. We analyzed the association of clinical and laboratory variables with DVT to evaluate the risk of DVT in patients after AIS.AIS patients admitted to the Changsha Central Hospital between January 2017 and December 2019 with length of stay in hospital ≥7 days were included. Clinical and laboratory variables for DVT at baseline were collected, and the diagnosis of DVT was confirmed by ultrasonography. Independent factors were developed by Multivariate logistic regression analysis.A total of 101 patients were included in the study. The in-hospital incidence of DVT after AIS was 19.8%(20/101). The average level of D-dimer when DVT detected was significant increased around 4-fold than that on admission (P < .001). Pulmonary infection (odds ratio [OR] = 5.4, 95%CI:1.10–26.65, P = .037)) and increased muscle tone (OR = 0.11, 95%CI:0.02–0.58, P = .010) as independent relevant factors for DVT were confirmed.Pulmonary infection as a risk factor and increased muscle tone as a protective factor for DVT were identified in patients after AIS. The level of D-dimer which increased around 4-fold compared to the initial level could be an indicator for DVT occurrence.     

急性脑梗死患者血小板聚集功能、血管性血友病因子、抗凝血酶及 D-二聚体测定的临床意义

目的：探讨急性脑梗死患者血小板聚集功能（ PAgT）、血管性血友病因子（ vWF）、抗凝血酶（ AT）和D-二聚体（ D-dimer）水平变化及临床意义。方法选用相应的方法和仪器测定112例脑梗死及80例健康对照者血（浆） PAgT、vWF、AT和D-dimer水平变化,同时对部分患者进行治疗前、后的对比分析。结果脑梗死患者血中PAgT、vWF、D-dimer等指标均明显高于健康对照组,AT活性较对照组显著降低,差异有统计学意义（P＜0．05或P＜0．01）。选取经治疗效果明显好转的78例脑梗死患者,出院前取空腹静脉血测定PAgT、vWF、AT、D-dimer等指标,并与治疗前对照,结果治疗后PAgT、vWF、D-dimer降低,AT活性升高,差异有统计学意义（P＜0．05或P＜0．01）。结论脑梗死患者体内存在明显的凝血及纤溶功能异常,与血管内皮损伤、血小板聚集功能增强、凝血及纤溶功能亢进、抗凝功能降低等多因素有关。 PAgT、vWF、AT、D-dimer可以作为脑梗死患者诊断、治疗监测和预后判断的参考指标。     

High pretreatment D-dimer level is an independent unfavorable prognostic factor of small cell lung cancer: A systematic review and meta-analysis

Background:High pretreatment level of D-dimer in small cell lung cancer (SCLC) is commonly encountered, but the impact of high pretreatment D-dimer level on the prognosis of SCLC patients remains undetermined. Therefore, we conducted this meta-analysis focusing specifically on the prognostic value of high pretreatment D-dimer level in SCLC patients comprehensively.Methods:We searched systematically in PubMed, Embase, and Web of Science for relevant studies published before January 28, 2019. Outcomes including 1-year overall survival (OS), progression-free survival (PFS) rates, and hazard ratios (HRs) of OS and PFS from multivariate analysis were extracted and analyzed.Results:A total of 5 cohort studies consisting of 813 SCLC patients (473 patients with high pretreatment level of D-dimer and 340 with normal level of D-dimer) were finally included for meta-analysis. We found that patients with high pretreatment level of D-dimer had significantly shorter 1-year OS (47.6% vs 79.9%; fixed effects: risk ratio [RR] = 2.506; 95% confidence interval [CI] = [1.948, 3.224]; P < .001) and PFS (15.8% vs 34.0%; random effects: RR = 1.294; 95% CI = [1.060, 1.579]; P = .011) rates than those with normal level of D-dimer. Moreover, high pretreatment D-dimer level was further proved to remain as an unfavorable predictor of OS (fixed effects: HR = 1.865; 95% CI = [1.469, 2.367]; P < .001; I² = 7.6%) and PFS (fixed effects: HR = 1.513; 95% CI = [1.183, 1.936]; P = .001; I² = 0.0%) in patients with SCLC.Conclusion:High pretreatment level of D-dimer was found to be an independent unfavorable prognostic factor in SCLC patients. However, more studies with sufficient adjustment for confounding factors are encouraged to confirm our conclusions.     

Imbalance of tissue-type plasminogen activator (t-PA) and its specific inhibitor (PAI-1) in patients with rheumatoid arthritis associated with disease activity

Summary The relationship between plasma fibrinogen, D-dimer (DD), t-PA and PAI-1 and their correlation with disease activity (DA) were studied in 45 patients with rheumatoid arthritis (RA) (group B) to further understand the implication of fibrinolysis in the pathophysiology of RA. The control group constituted 24 healthy subjects (group A). A Stoke index (SI) of DA was assigned to each patient. Patients were divided into two groups: C, minimal-mild DA (SI 1–7); D, moderate-severe DA (SI 8–17). Fibrinogen was elevated in RA correlating positively with SI and CRP. Hypercoagulability counteracted by reactive fibrinolysis was inferred from a 10-fold increase of DD in group B as compared to group A. The relatively lower levels of DD in group D compared to group C and their negative correlation with SI (r_s=–0.45, –0.49, p=0.0006) indicate the tendency of fibrinolysis to decrease with the increase of DA. Significant elevation of t-PA and PAI-1 were found in group B compared to group A. While t-PA progressively decreased with the increase of DA (r_s=–0.45, p=0.0019), a positive relation of PAI-1 to DA was observed (r_s=0.42, p=0.0042). A 2-fold increase of PAI-1/t-PA molar ratio in group D compared to groups A and C as well as its positive correlation with SI (r_s=0.63, p=0.0001) indicate the displacement of balance between t-PA and PAI-1 in favour of the inhibitor with the increase of DA in RA. The involvement of inflammatory mediators in PAI-1/t-PA imbalance was proposed from the relation of fibrinolytic abnormalities with the activity of systemic inflammatory process.     

冠心病患者D-二聚体的变化及其与血脂异常的相关研究

目的:通过检测血浆D-二聚体(D-dimer,DD)水平以评估不同类型冠心病患者体内新鲜血栓形成的可能性,并研究此类改变与诸血脂指标的相关关系。方法:对124例不类型的冠心病患者与26例正常人分别采用ELISA法测定血浆DD水平和脂蛋白(a)[Lp(a)],酶法测定甘油三酯(TG)、胆固醇(TC)和高密度脂蛋白(HDL),免疫散射比浊法测定载脂蛋白A1(ApoA1)和载脂蛋白B(ApoB)水平。结果:(1)与对照组比较,稳定型心绞痛(SAP)、陈旧性心肌梗死(OMI)组患者DD水平未改变(P>0.05),急性心肌梗死(AMI)组患者DD水平升高非常显著(P<0.01),不稳定型心绞痛(UAP)组患者DD水平亦显著升高(P<0.05),AMI组DD水平显著高于UAP组(P<0.05);与SAP、OMI组比较,UAP、AMI组DD水平升高显著(P<0.05);(2)DD与TG、ApoB和[Lp(a)]呈明显正相关(r=0.393,0.650和0.579,P<0.001);与TC亦呈正相关关系(r=0.235、P=0.009);与ApoA1和HDL呈负相关(r=-0.496,-0.178,P<0.001,P<0.05);(3)多元逐步回归可见ApoB和Lp(a)为独立影响DD的血脂指标。结论:在AMI、UAP组患者中,有与新鲜血栓形成相关指标DD的增高,以AMI组更为严重;血脂异常对冠心病患者的DD水平有影响,其中ApoB和Lp(a)为独立影响DD的血脂指标。     

Antiangiogenic Treatment of Mesenteric Desmoid Tumors With Toremifene and Interferon Alfa-2b: Report of Two Cases

PURPOSE: Desmoid tumors are uncommon, benign, fibrous lesions occurring sporadically and in association with familial adenomatous polyposis. Typical clinical features include a locally aggressive behavior, an unpredictable course, and a high propensity for recurrence after surgical resection. There are no standard medical or surgical approaches, and no markers for monitoring medical therapy of desmoid tumors. METHODS: We report two cases of mesenteric desmoid tumors treated with interferon alfa-2b and toremifene, a novel regimen devised to block angiogenesis. Pre- and posttreatment desmoid tumor tissues were obtained in one patient during a repeat resection for recurrent stenosing Crohns disease and examined for mean vessel count and cellular proliferation levels by immunostaining for the endothelial surface antigen CD31 and the proliferation associated nuclear antigen, Ki-67, respectively. We assessed plasma D-dimers, a potential marker of angiogenic activity, and followed this throughout the course of antiangiogenic therapy in our two patients. RESULTS: Examination of posttreatment tissue revealed a significant decrease in microvessel density (P < 0.02) and Ki-67-positive nuclei (P < 0.0001) compared with pretreatment tissue. Both patients demonstrated a prompt and sustained drop in previously elevated plasma D-dimer levels, which correlated clinically with lesion regression and sustained remission. CONCLUSIONS: Treatment with toremifene and interferon alfa-2b was successful and well tolerated in our two patients. Our data suggest a combined antiangiogenic and antiproliferative mechanism of action. Furthermore, normalization of previously elevated plasma D-dimers may emerge as a strategy to monitor treatment efficacy in mesenteric desmoid tumors.     

血浆D-二聚体和VWF测定在肺癌诊治中的研究

本文用ELISA法测定了51例肺癌患者血浆D—二聚体和VWF化疗前后含量。结果肺癌患者化疗前D—二聚体和VWF含量显著高于正常对照组及良性肺病组(P<0.001)。治疗缓解的患者血浆D—二聚体和VWF含量明显低于治疗前(P<0.01),治疗无效或恶化者血浆D—二聚体和VWF含量持续在高值或进一步升高。肺癌患者当伴有感染和/或咯血时,血浆D—二聚体和VWF含量比无感染和/或咯血并发症时显著增高。结果提示血浆D—二聚体和VWF的测定对肺癌的诊断、判断疗效和监测疾病进展有重要价值。