Reduction In D-dimer Research Articles

Abstract 13200: Changes in Thrombi-Inflammatory Biomarkers Associated With Therapeutic Heparin in Non-Critically Ill Patients Hospitalized With COVID-19: A Pre-Specified Secondary Analysis of the ACTIV4a and ATTACC Randomized Clinical Trial

Background: SARS-CoV-2 infection potentiates thromboinflammation contributing to poor outcomes in COVID-19. In non-critically ill patients hospitalized for COVID-19, therapeutic-dose heparin improves clinical outcomes. We hypothesized therapeutic-dose heparin impacts thromboinflammatory biomarkers in patients hospitalized for COVID-19 infection. Methods: We conducted a pre-specified secondary analysis of a multi-platform open-label, randomized trial comparing therapeutic-dose versus usual-care thromboprophylaxis-dose heparin in non-critically ill patients hospitalized for COVID-19. Inflammatory markers were analyzed using Wilcoxon rank-sum test and compared based on treatment. Ordinal logistic regression models evaluated for relative D-Dimer change (measured at baseline, day 1, day 3). Odds ratio of a 3-level ordinal outcome (death, survival with organ support, or survival without organ support through 21 days) was determined for relative change. Results: Of 1510 patients, 528 had a D-Dimer on baseline and day 1, and 432 on baseline and day 3. Median age was 60 years (IQR: 50-69) with 41% female and 66% under-represented minorities. Compared to usual-care, therapeutic-dose heparin was associated with a greater drop in D-Dimer at days 1 and 3; other biomarkers were unaffected by treatment (Table 1). D-Dimer at baseline and day 1 had an OR 0.93 (95% CI: 0.88, 0.98) whereas baseline and day 3 had an OR 0.86 (95% CI: 0.78, 0.94) of the ordinal outcome translating in a higher odds of surviving without the need for organ support (adjusted for treatment, gender, and age). Conclusion: In this randomized controlled trial therapeutic-dose heparin was associated with an early reduction in D-Dimer and clinical improvement, suggesting thromboinflammatory mechanisms whereby treatment conferred a clinical benefit. Temporal changes in D-dimer could predict treatment response or may signal need for alternative therapies.

THE ROLE OF HERBAL IMMUNOMODULATORS AS ADJUVANT THERAPY FOR ASYMPTOMATIC AND MILDLY SYMPTOMATIC COVID-19: AN EXPLORATORY CLINICAL STUDY

Objectives: The objective of the study is to evaluate herbal immunomodulators (Septilin and Bresol) as a possible adjuvant therapy for the treatment of asymptomatic and mildly symptomatic COVID-19. Methods: Randomized, open-label, comparative clinical study. Subjects were randomized to either arm I [Septilin and Bresol+standard of care (SOC)] or arm II (SOC). This study was registered on CTRI (CTRI/2020/06/025801). Results: Subjects in arm I showed a greater reduction in levels of interleukin-6 tumor necrosis factor-α following treatment than in arm II. Subjects in arm I showed a greater increase in levels of interferon (IFN)-β and IFN-λ than those in arm II. There was a greater reduction in D-dimer in arm I than in arm II subjects (64.28% vs. 35.59%) and all arm I subjects had D-dimer values in the normal range compared to 70% of arm II subjects. There were statistically significant reduction in lactate dehydrogenase and neutrophil-to-lymphocyte ratio in arm I (p<0.016 and p<0.013, respectively). Clinical assessments during the post-illness convalescence period showed significant improvements in fatigue assessment scores and quality of life. Conclusion: This herbal combination as an adjuvant to SOC may provide additional long-term benefits in COVID-19 infection by reducing inflammation. This treatment may offer a good addendum for the management of post-COVID-19 illness.

КОМПЛЕКС ПРОФІЛАКТИЧНИХ ЗАХОДІВ ДЛЯ ВАГІТНИХ ПІСЛЯ ДРТ З ВИСОКИМ РИЗИКОМ ПРЕЕКЛАМПСІЇ

The purpose of the study: to evaluate the effectiveness of the proposed set of preventive measures for pregnant women after ART with a high risk of preeclampsia. Material and methods. To test the effectiveness of the proposed set of prophylactic measures, 60 pregnant women after ART were selected, which were randomly divided into 2 groups: 30 women who received the recommended complex (main group) and 30 women (comparison group), whose preeclampsia was prevented by order of the Ministry of Health. № 417 "Guidelines for the provision of outpatient obstetric and gynecological care." Results. The use of the recommended measures improves lipid metabolism (significant reduction of triglycerides and low density cholesterol), eliminates vitamin D deficiency, balances the cytokine profile (reduction of proinflammatory focus), reduces the prothrombotic potential of the hemostasis system (reduction of D-dimer and background marker damage). Improving the general condition and the use of psychotherapy can reduce the manifestations of vegetative-vascular dystonia, anxiety and improve quality of life. Such changes provide a more favorable background for the development of gestation. The incidence of preeclampsia decreased by 43.8% (from 26.7 to 15.0%), and mainly due to early preeclampsia, the incidence of which decreased by 78%, no cases of severe preeclampsia were reported. The frequency of placental insufficiency, fetal distress and growth retardation is reduced. The frequency of birth of children in a state of asphyxia is reduced by 2 times (up to 20.0 vs. 46.7%), severe asphyxia is not observed. Significantly lower and the frequency of violations of the period of neonatal adaptation (30.0 vs. 53.3%). Conclusions. The use of treatment and prophylactic complex to prevent preeclampsia in pregnant women after ART can improve a woman's homeostasis, balance vegetative-vascular regulation, reduce the incidence of preeclampsia by 43.8% (from 26.7 to 15.0%) and other complications of pregnancy and childbirth, improve perinatal outcomes. Proven medical, social and economic efficiency of the developed complex allows to recommend it for implementation in medical practice.

Efeitos da suplementação com probióticos em pacientes com o vírus da imunodeficiência humana: revisão sistemática.

Objetivo: É de conhecimento que certos micro-organismos melhoram a função da barreira intestinal, que por sua vez é atingida pela infecção pelo (HIV). Esta revisão teve como objetivo identificar os possíveis efeitos da suplementação com probióticos em pacientes acometidos peloVírus da Imunodeficiência Humana (HIV). Métodos: Foram utilizadas as bases de dados do MEDLINE/PubMed e Lilacs publicados na língua inglesa, no período 2008 a 2018, com os descritores “probiotics” AND “HIV”. Foram incluídos ensaios clínicos randomizados realizados em indivíduos adultos acometidos pelo HIV, que tenham feito uso de probióticos. Foram excluídos artigos não-originais e trabalhos em outro idioma que não a língua inglesa, além de estudos com animais ou in vitro e ainda estudos em gestantes, lactentes e pessoas com idade inferior a 18 anos. Resultados: Do total de 149 artigos encontrados, 10 obedeceram aos critérios de inclusão. As principais cepas utilizadas foram do gênero Lactobacillus e Bifidobacterium. Os principais achados dos estudos estão relacionados à redução da translocação bacteriana e inflamação, aumento do número de células T CD4+ e redução do D-dímero, bem como melhora dos sintomas gastrointestinais. Conclusões: Existem evidências de que a suplementação com probióticos possa ser recomendada na prática clínica como adjuvante da terapia antiretroviral. Entretanto, em decorrência da complexidade do assunto e de os estudos nessa temática serem escassos e heterogêneos, faz-se necessários mais estudos a fim de determinar cepas, tempo de intervenção, dosagens, bem como a efetividade do uso de probióticos por pacientes com HIV.

Correlation of coagulation markers with axillary lymph node metastasis in breast malignancy: a tertiary care centre study in North India

Background: Breast cancer is the most common female cancer worldwide representing nearly a quarter (25%) of all cancers. Search for a marker which can predict lymph node metastasis in clinically negative axilla has been a matter of research for long. The present study is an attempt to evaluate role of coagulation makers with special reference to D-dimer and factor 7 and 8 in patients of carcinoma breast in predicting lymph node metastasis in carcinoma patients.Methods: The study was a prospective study conducted in 50 diagnosed patients of carcinoma breast in whom D dimer levels and factor 7 and 8 levels were measured at the time of commencement of the treatment and at six weeks after surgery.Results: Most of the patients in the study group were in the age group 41-70 (80%) years. 22% patients were of early Breast cancer. The reduction in D-dimer, factor VII and factor VIII value after 6 weeks of surgery were significant (p value 0.0001 for all three).Conclusions: D-dimer and factor VII were found to be an independent predictive factor for lymph node metastatsis, thus providing as a safe, easy, objective and convenient supplement to sentinel node biopsy in assessing metastatic disease in axilla. Combined- with other biomarkers, it may prove to be an alternative to sentinel node biopsy in assessing metastatic disease in axilla. Significant postoperative decrease in D-dimer, factor VII and factor VIII may provide objective criteria to assess completion of surgery.

Targeting Protein Disulfide Isomerase with the Oral Flavonoid Isoquercetin Prevents Venous Thromboembolism in Advanced Cancer: Results of a Multi-Dose, Multi-Center, Phase II Clinical Trial (CATIQ Study)

▪BackgroundProtein disulfide isomerase (PDI) is a thiol isomerase secreted by platelets and endothelial cells and is required for thrombus formation. We previously showed that quercetin flavonoids inhibit PDI and block thrombus formation following vascular injury in a mouse model. Quercetins are present in a wide range of fruits and vegetables and epidemiologic data suggest an antithrombotic effect. Initial human studies demonstrated that the oral administration of isoquercetin reduces PDI activity in plasma. To evaluate the antithrombotic strategy of inhibiting PDI, we performed a phase II trial to evaluate the efficacy of isoquercetin to reduce the hypercoagulability of cancer patients at high risk for venous thromboembolism (VTE). In high-risk cancer cohorts with protocol-mandated screening for VTE, the reported incidence of VTE often exceeds 20% within months of initiation of chemotherapy. The risk of major hemorrhage is also higher in patients with advanced cancer which complicates the decision to recommend thromboprophylaxis.MethodsWe performed a phase II study at 11 sites to assess the safety and efficacy of isoquercetin in cancer patients at high risk for VTE. Cohort A received isoquercetin 500 mg daily and Cohort B received 1000 mg isoquercetin daily for 56 days with laboratory assays performed at the beginning and at completion of study. Eligible patients had locally advanced or metastatic pancreatic, non-small cell lung, or colorectal cancer and enrolled within 4 weeks of initiating first or second line chemotherapy. The primary endpoint of the study was a reduction in D-dimer at day 56. Patients were monitored for the development of venous thromboembolism including a protocol-required bilateral lower extremity ultrasound performed at day 56. The primary VTE endpoint was defined as any symptomatic proximal or distal lower extremity DVT, symptomatic pulmonary embolism or fatal PE, or asymptomatic proximal DVT diagnosed by screening compression ultrasound. Radiology images for all suspected VTE were centrally reviewed and adjudicated by an independent committee.ResultsThere were no primary VTE endpoints observed in either cohort. Paired plasma samples were analyzed in 25 patients who received isoquercetin 500 mg daily (Cohort A) and 21 patients who received the isoquercetin 1000 mg daily (Cohort B). For the primary D-dimer endpoint, the administration of isoquercetin 1000 mg decreased D-dimer plasma concentrations by a median of 20% equating to a median decrease of 206 ng/ml fibrinogen equivalent units (P<0.001). The administration of isoquercetin 500 mg did not affect plasma D-dimer levels at 56 days (median change +9.90%, P=0.93). In both cohorts we measured an increase in PDI inhibition in plasma at day 56 (cohort A median increase 46%, P<0.001; cohort B median increase 78%, P<0.001). Corroborating the antithrombotic efficacy of the 1000 mg dose, we also observed a significant decrease in circulating soluble P-selectin (median decrease 58%, P<0.001) and platelet-dependent thrombin generation (median decrease 55%, P=0.006) as shown in the Figure. Isoquercetin did not prolong the PT or PTT. There were two grade 1 hemorrhoidal bleeds and no major hemorrhages observed.ConclusionsThe oral flavonoid, isoquercetin, prevented venous thromboembolism in cancer without an observed increase in hemorrhage. These results represent the first evidence in humans that targeting extracellular PDI has antithrombotic efficacy in a high VTE-risk population and implicate PDI-targeted therapies as a new class of antithrombotic therapeutics. (Clinicaltrials.gov #NCT02195232). DisclosuresZwicker:Daiichi: Honoraria; Quercegen: Research Funding; Parexel: Consultancy; Incyte: Research Funding.

D-dimer and factor VIIa in atrial fibrillation - prognostic values for cardiovascular events and effects of anticoagulation therapy. A RE-LY substudy.

Coagulation markers may improve monitoring the risk of stroke and bleeding in patients with atrial fibrillation (AF) during anticoagulant treatment. We examined baseline levels of D-dimer and their association with stroke, cardiovascular death and major bleeding in 6,202 AF patients randomised to dabigatran or warfarin in the RE-LY trial. The effects of treatment on serial levels of D-dimer and coagulation factor (F) VIIa in 2,567 patients were also analysed. Baseline D-dimer levels were related to the rate of stroke/systemic embolism (SEE) with 0.64 % in the lowest quartile (Q1, as reference) (D-dimer < 298 µg/l), 1.38 % Q2 (D-dimer 298-473 µg/l), 1.71 % Q3 (D-dimer 474-822 µg/l) and 2.00 % in Q4 (D-dimer > 822 µg/l) (p=0.0007). Similar associations were shown for cardiovascular death and major bleeding. Addition of baseline D-dimer to established clinical risk factors improved prediction of stroke/SEE, cardiovascular death and major bleeding (C-index increased from 0.66 to 0.68, 0.71 to 0.73 and 0.66 to 0.67, respectively). Dabigatran provided a greater reduction of D-dimer levels than warfarin regardless of baseline anticoagulant treatment. On-treatment levels of FVIIa were markedly reduced by warfarin (median 12.1-13.8 mU/ml) but significantly higher with dabigatran (median 39.4-49.0 mU/ml) at all-time points. Dabigatran is associated with greater reduction in D-dimer without the pronounced reduction of FVIIa seen with warfarin. These different effects on the coagulation system might explain the better efficacy and less intracranial bleeding observed with dabigatran compared with warfarin.

D-dimer and factor VIIa in atrial fibrillation – prognostic values for cardiovascular events and effects of anticoagulation therapy

SummaryCoagulation markers may improve monitoring the risk of stroke and bleeding in patients with atrial fibrillation (AF) during anticoagulant treatment. We examined baseline levels of D-dimer and their association with stroke, cardiovascular death and major bleeding in 6,202 AF patients randomised to dabigatran or warfarin in the RE-LY trial. The effects of treatment on serial levels of D-dimer and coagulation factor (F) VIIa in 2,567 patients were also analysed. Baseline D-dimer levels were related to the rate of stroke/systemic embolism (SEE) with 0.64 % in the lowest quartile (Q1, as reference) (D-dimer &lt; 298 μg/l), 1.38 % Q2 (D-dimer 298–473 μg/l), 1.71 % Q3 (D-dimer 474–822 μg/l) and 2.00 % in Q4 (D-dimer &gt; 822 μg/l) (p=0.0007). Similar associations were shown for cardiovascular death and major bleeding. Addition of baseline D-dimer to established clinical risk factors improved prediction of stroke/SEE, cardiovascular death and major bleeding (C-index increased from 0.66 to 0.68, 0.71 to 0.73 and 0.66 to 0.67, respectively). Dabigatran provided a greater reduction of D-dimer levels than warfarin regardless of baseline anticoagulant treatment. Ontreatment levels of FVIIa were markedly reduced by warfarin (median 12.1–13.8 mU/ml) but significantly higher with dabigatran (median 39.4–49.0 mU/ml) at all-time points. Dabigatran is associated with greater reduction in D-dimer without the pronounced reduction of FVIIa seen with warfarin. These different effects on the coagulation system might explain the better efficacy and less intracranial bleeding observed with dabigatran compared with warfarin.Clinical Trial Registration: NCT00262600 (www.clinicaltrials.gov).Supplementary Material to this article is available online at www.thrombosis-online.com.

Antioxidant and Anticoagulant Status Were Improved by Personalized Dietary Intervention Based on Biochemical and Clinical Parameters in Cancer Patients

We investigated whether personalized dietary intervention could improve clinical measurements such as immune cell-mediated cytotoxicity, serum albumin, derivatives of reactive oxygen metabolites (D-ROMS), D-dimer, and fibrinogen. Cancer patients received either a treatment support diet (TD, for those with chemotherapy), or a remission support diet (RD; for those in remission) for at least 3 wk (21–61 days). Both diets were low glycemic, low fat, and high plant protein diets; the diet for the TD group contained an additional 0.5 servings of protein. Based on clinical values, additional amounts of garlic, onion, tomato, shiitake, rice bran, kale, blueberry, pineapples, and/or turmeric powder were provided in regular meals. Estimated daily intake of protein, plant fat, garlic, onion, allicin, and quercetin was greater in the TD compared to the RD. An increased intake of vitamin A, vitamin C, vitamin E and selenium and a reduction in D-dimer were noted compared to baseline diets in both groups. A decrease in D-ROMS in the RD and an increase in albumin and an increased tendency in cytotoxicity in the TD were observed. In conclusion, personalized diets with supplemented functional ingredients improved antioxidant status and/or anticoagulant activity in cancer patients undergoing chemotherapy and in remission.

Biomarker response to drotrecogin alfa (activated) in children with severe sepsis

REsearching severe Sepsis and Organ dysfunction in children: A gLobal perspective (RESOLVE), a phase III trial of drotrecogin alfa (activated) in pediatric severe sepsis, examined biomarker changes in inflammation and coagulation. This report describes biomarker profiles in early severe sepsis and the pharmacodynamic assessment of drotrecogin alfa (activated) in RESOLVE. Serial measurements of interleukin-1β, interleukin-6, interleukin-8, interleukin-10, tissue necrosis factor-α, procalcitonin, D-dimer, and thrombin-antithrombin complex were performed at baseline and daily over the first five study days. Protein C levels were performed at baseline and at the end of the 96-hr study drug infusion. Analysis of variance-based log-transformed data compared the treatment groups for each measured variable. : One hundred four pediatric intensive care units in 18 countries. Four hundred seventy-seven children between 38 wks corrected gestational age and 17 yrs with sepsis-induced cardiovascular and respiratory dysfunction. Drotrecogin alfa (activated). Pharmacodynamic activity of drotrecogin alfa (activated) compared with placebo was observed with reduction of D-dimer on day 1 (p < .01) and thrombin-antithrombin complex on days 1-4 (p < .05). There were no significant changes by treatment in multiple cytokines or procalcitonin. In the overall population, a median protein C difference was not observed (p > .05) with drotrecogin alfa (activated) administration compared with placebo, although a difference (median percentage change from baseline) in favor of drotrecogin alfa (activated) was observed in patients >1 yr old (p = .0449). While children in the RESOLVE trial were similar to adults in that they showed a relationship between severity of coagulation and inflammation abnormalities and mortality, their pharmacodynamic response to drotrecogin alfa (activated) differed with respect to changes in protein C activity and systemic inflammation.

Eculizumab therapy results in rapid and sustained decreases in markers of thrombin generation and inflammation in patients with PNH independent of its effects on hemolysis and microparticle formation

Paroxysmal Nocturnal Hemoglobinuria (PNH) is a clonal bone marrow disorder which results in the loss of glycosylphosphatidyl inositol (GPI) anchors from cell membranes. As a consequence, membrane inhibitors of complement are lost rendering the cells more susceptible to complement mediated destruction. This results in hemolysis, leukopenia, thrombocytopenia and thrombophilia. Eculizumab, a monoclonal antibody to complement protein 5, has been approved for the treatment of PNH and is associated with a significant reduction in hemolysis, thromboembolic events and fatigue. We prospectively studied the effect of Eculizumab therapy on plasma markers of thrombin generation (D-Dimers, TAT), inflammation (IL-6), soluble P-selectin (sP-selectin), antigenic (TFMP) and functional (fTFMP) tissue factor bearing microparticles and total plasma microparticle ex vivo factor Xa generation (MPFXa) in eleven Eculizumab naive PNH patients. Blood sampling occurred day 1, prior to Eculizumab treatment, then on days 8,15,22,29, 43, 90. Our results demonstrate a statistically significant reduction in D-Dimer, TAT, IL-6, sP-selectin, and TFMP during the induction phase of treatment (day 1–29) which was sustained during the maintenance treatment (day 29–90). Although the serum LDH levels decreased rapidly, there was no correlation between the change in LDH and the markers of thrombin generation and inflammation. Although there was a statistically significant decrease in TFMP, this decrease did not correlate with changes in markers of thrombin generation or inflammation. Ex vivo MPFXa generation did not decrease with Eculizumab treatment suggesting continued microparticle formation despite inhibition of hemolysis. Ex vivo total microparticle FXa generation was found to have an inverse correlation with markers of thrombin generation, suggesting that in PNH patients in vivo thrombin generation occurs by a pathway independent of hemolysis and microparticle generation.

Correlation of D dimer and factor VIII levels with histopathology in patients with breast carcinoma

There is evidence that the components of the coagulation/fibrinolytic system play a role in cancer biology and angiogenesis. Studies reveal that at the time of diagnosis, majority of the cancer patients have laboratory evidence of systemic coagulation activation. Our purpose was to investigate the significance of D-Dimer (product of fibrin degradation) and factor VIII levels in breast cancer and to evaluate its relationship with other variables such as histological characteristics, lymph node status and immunohistochemistry markers (ER, PR and Her-2neu). A prospective study was conducted in the Department of Surgery in collaboration with Departments of Medicine, Pathology and Radiodiagnosis & Imaging, Maulana Azad Medical College & Lok Nayak Hospital, New Delhi. Fifty patients with diagnosed cancer breast who were treated in surgery department were evaluated for D Dimer and factor VIII levels. D-dimer and Factor VIII levels were measured three times i.e. at the time of commencement of treatment then after three cycles of Chemotherapy (CAF Regimen) and finally after six weeks of surgery. Significantly higher levels of D Dimer and factor VIII were observed in tumors with significant lymphovascular and adipose tissue invasion in comparison to localized tumors. The reduction in D-dimer and Factor VIII values after Surgery was significant for both D-dimer (p value 0.000) and Factor VIII (p value 0.000). The reduction in D-dimer after 3 cycles of chemotherapy was significant for D-dimer (575.51 ± 572.47 ng/ml vs. 422.45 ± 363.58 ng/ml; p value 0.046) but not significant for Factor VIII (307.83 ± 184.47 ng/ml vs. 288.78 ± 163.02 ng/ml; p value 0.151). D-dimer and factor VIII may be used as yardstick for systemic adjuvant therapy in node negative < 1 cm breast cancer. D-dimer may prove to be a safe, convenient and easily available biomarker which can be combined with conventional sentinel node biopsy in clinically node negative breast cancer to assess metastatic disease in axilla and reduce false negative results.

Apixaban decreases coagulation activity in patients with acute deep-vein thrombosis

In patients with acute deep-vein thrombosis (DVT), apixaban, a direct oral factor Xa inhibitor, showed efficacy and safety similar to low-molecular-weight heparin followed by vitamin K antagonist (LMWH/VKA). We evaluated biomarkers of coagulation activity in relation to treatment dose, duration and clinical outcome. Patients (N = 520) with symptomatic DVT were randomised to receive apixaban (5 mg bid, 10 mg bid or 20 mg qd) or LMWH/VKA for 12 weeks. Plasma D-dimer, prothrombin fragment 1+2 (F1+2) and thrombin-antithrombin complex (TAT) levels were measured at baseline, and weeks 3 and 12 after treatment. Median plasma levels of D-dimer, F1+2 and TAT were elevated at baseline. At weeks 3 and 12, biomarker levels were normalised in most patients in all treatment groups, consistent with the low rate of venous thromboembolism (VTE) observed. Median reduction in D-dimer was similar in all treatment groups; percentage of patients with D-dimer above upper limit of normal decreased from 95% to 24-40% at week 12. F1+2 decline was greater with LMWH/VKA than apixaban. F1+2 in the apixaban groups changed to a similar extent (>84% of patients had F1+2 within reference range at week 12). Magnitude of TAT reduction was not quantifiable. In conclusion, levels of coagulation biomarkers decreased over 12 weeks of treatment with apixaban or LMWH/VKA in most patients with acute VTE. Baseline D-dimer and F1+2 were higher in patients with recurrent symptomatic VTE than in those without. Plasma levels of coagulation biomarkers did not appear to correlate with total bleeding events.

Atherothrombosis and oxidative stress: the connection and correlation in diabetes

Background: Hyperglycaemia-induced depletion of reduced glutathione (GSH) causes erythrocyte oxidative stress (EOS), which leads to vascular events including exacerbation of thrombotic events evidenced by changes in D-dimer level. It would, therefore, appear that there is a complex link between GSH and D-dimer, which are part of an emerging array of biomarkers associated with diabetes. The objective of this study was to investigate evidence of correlation between levels of plasma D-dimer and erythrocyte GSH in diabetes disease progression.Subjects and methods: A cohort of 69 subjects were selected based on medical history plus clinical findings and equally divided into control, prediabetes and diabetes groups, matched for age and sex. Plasma D-dimer and erythrocyte reduced glutathione (GSH) were determined and separated into quartiles as a means of indicating disease severity. Statistical analysis was by Pearson's correlation coefficient.Results: Of the three groups, only the diabetes group showed any correlation between GSH and D-dimer. Of importance is that for increasing GSH, the second quartile range of GSH (xbar ± SD = 45 ± 22 mg/100ml) showed a statistically significant negative correlation for ranked D-dimer (xbar ± SD = 1055 ± 828 μg/l; r = −0.88; P < 0.02). The fourth quartile GSH range (xbar ± SD = 79 ± 40 mg/100 ml) showed a statistically significant positive correlation with D-dimer (xbar ± SD = 1055 ± 828 μg/l; r = 0.91; P < 0.02). Thus, within the diabetes group only, the increasing level of oxidative stress as measured by GSH first indicates a reduction in D-dimer followed by a rise in D-dimer, which led to the proposal of a two-part process of atherosclerosis that reconciles previous contradictory findings.Conclusions: This study provides not only evidence of a correlation between oxidative stress level and fibrinolysis in diabetes, but also an explanation of why previous studies have found both hypo- or hyperfibrinolysis associated with diabetes.

Randomized trial of different regimens of heparins and in vivo thrombin generation in acute deep vein thrombosis

AbstractLow-molecular-weight and unfractionated heparins are frequently used to treat venous thromboembolism, but it is not known whether they are equally effective in inhibiting in vivo generation of thrombin. In this multicenter trial, 1048 patients were randomized to intravenous unfractionated heparin (group A), twice daily low-molecular-weight heparin (reviparin) for 1 week (group B), or once daily reviparin for 4 weeks (group C). All patients received vitamin K antagonists. Blood samples withdrawn at the baseline and at weeks 1 and 3 were analyzed using markers of in vivo thrombin generation and other coagulation parameters. During the first 3 weeks symptomatic recurrent deep vein thrombosis–pulmonary embolism (DVT/PE) occurred in 17 (4.5%) of 375 patients in group A compared with 4 (1.0%) of 388 patients in group B, and 9 (2.4%) of 374 patients in group C. Forty percent of patients in group A, 53.4% in group B, and 53.5% in group C showed 30% or greater reduction in thrombus size assessed by venography. Patients in group B had significantly greater reduction in D-dimer, prothrombin fragments 1 and 2 (F1 + 2), endogenous thrombin potential (ETP), and thrombin-antithrombin (TAT) complexes compared to groups A and C. Greater release of tissue factor pathway inhibitor (TFPI) and reduction in levels of thrombin activatable fibrinolysis inhibitor (TAFI) and fibrinogen were significantly more pronounced in group C patients. Reviparin administered twice daily plus vitamin K antagonist is more effective in inhibiting in vivo thrombin generation compared to intravenous unfractionated heparin plus vitamin K antagonist, and reviparin once daily produced significantly higher TFPI release and greater reduction in TAFI and fibrinogen levels.

Protein C pathway in sepsis

The goals of this chapter are to provide a brief review of the biology of the protein C pathway and some of the features of the pathway that make it uniquely positioned to control microvascular coagulation and control the acute inflammatory response. Activated protein C works as an antithrombotic agent by inactivating factors Va and VIIIa. It is particularly effective at preventing microvascular thrombosis. Platelets may provide a margin of safety for activated protein C as an antithrombotic. Approximately 25% of the factor V/Va in plasma is contained within the platelet and hence resistant to time dependent inactivation by activated protein C. In addition, factor Va bound to the platelet surface is relatively resistant to inactivation by activated protein C. Activated protein C also facilitates clot lysis by inhibiting plasminogen activator inhibitor 1, a process that is accelerated markedly by vitronectin. Inflammatory cytokines like tumor necrosis factor f (TNF f ) and interleukin1 g (IL-1 g ) downregulate two key components of the protein C activation complex, thrombomodulin and the endothelial cell protein C receptor resulting in decreased protein C activation. Activated protein C in turn has been shown in several animal models and in vitro to inhibit TNF elaboration in response to endotoxin. This inhibition appears to be due to diminished nuclear factor s B (NF s B) expression and nuclear translocation. Activated protein C has been shown to reduce the rate of death due to severe sepsis. This reduction may be due to both the anticoagulant effects as demonstrated by a reduction in D-dimer and inflammatory effects as demonstrated by a reduction in interleukin 6.