Clinical Implications of Crosstalk Between Coagulation and Inflammation: The Role of Anticoagulation in Treating Sepsis

Abstract BACKGROUND: Despite decades of active investigation, sepsis remains one of the leading causes of mortality worldwide. Multiple lines of evidence have illustrated that up-regulation of the activated Factor VII (FVIIa)/Tissue Factor (TF) complex, and its downstream extrinsic coagulation cascade, are major contributors to coagulopathies and inflammatory response during sepsis. For example, decreased mortality and inflammatory responses during sepsis were observed in mice with significantly reduced FVII expression. Another recent study demonstrated the association of increased mortality with higher levels of FVIIa in septic patients. Similar results have been demonstrated for Factor X (FX) and thrombin. In addition, several studies have been conducted to investigate the role of heparin in treating sepsis and have yielded promising results, however, the exact mechanisms remain elusive, and the clinical implications of crosstalk between coagulation pathways and sepsis are yet to be determined. Furthermore, the role of vitamin-K antagonist in sepsis has not been investigated. OBJECTIVE: To assess the effects of pre-existing anticoagulation with warfarin on the clinical course of septic patient. METHODS: This was a retrospective observational study undertaken in a community-based teaching hospital. Patients who were admitted with a primary diagnosis of sepsis from January 01 to June 30, 2012 were included in the study. The clinical characteristics between patient groups without and with prior anticoagulation were compared and analyzed. The primary outcomes include the severity of sepsis, length of hospitalization, and mortality rate during hospitalization. RESULTS: A total of 134 septic patients were included in the study. Among them, 105 patients were not anticoagulated, while 29 patients were anticoagulated, prior to admission (mean age: 76.0 + 1.2 vs. 77.5 + 2.6, p = 0.603). All of the patients with anticoagulation had been taking warfarin due to either pre-existing atrial fibrillation (79.3%) or deep vein thrombosis/pulmonary embolism (20.7%). There were significant differences in International Normalized Ratio (INR) of prothrombin time between groups without and with anticoagulation at the time of admission (1.28 + 0.04 vs. 4.59 + 0.83, p < 0.001). Septic patients who did not take warfarin prior to admission presented with higher Sepsis Indices (0.93 + 0.03 vs. 0.82 + 0.05, p < 0.05), resulting in longer hospitalizations (11.60 + 1.02 vs. 8.40 + 0.70, p < 0.001). The overall all-cause mortality rates during the hospitalization between patients without anticoagulation and those with anticoagulation were 23% vs. 14%, respectively. CONCLUSION: To our knowledge, this is the first study to demonstrate that septic patients with prior anticoagulation by a vitamin-K antagonist presented with less severity of sepsis, reduced length of hospital stay, and decreased all-cause mortality during hospitalization as compared with those without anticoagulation. In our study, prior administration of anticoagulation with warfarin may have had significant clinical implications in septic patients. This warrants further prospective studies. Disclosures No relevant conflicts of interest to declare.

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The Activation of Human Factor X in Sodium Citrate: the Role of Factor VII

Thrombosis and Haemostasis ◽

10.1055/s-0038-1648014 ◽

1976 ◽

Vol 36 (01) ◽

pp. 104-114 ◽

Cited By ~ 3

Author(s):

D. L Aronson ◽

A. J Mustafa

Keyword(s):

Sodium Citrate ◽

Human Factor ◽

Deae Cellulose ◽

Factor Ix ◽

Factor Vii ◽

Factor X

SummaryHuman factor X was purified by several different procedures yielding products which had varying amounts of factor VII and factor IX. Treatment with CHC13 during the fractionation of the factor X removed 95% of the factor VII and factor IX activity and the resulting factor X activated more slowly when incubated in 25% sodium citrate. Removal of residual factor VII by DEAE cellulose chromatography yielded a factor X which activated still more slowly and less completely. When the factor VII, removed by chromatography, was added to the chromatographed factor X, the ability to be activated in 25% sodium citrate was restored. Confirmatory evidence for the role of factor VII in this reaction was the inhibition of the conversion of the factor X by both DFP and SBTI.

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Outcome of intracerebral hemorrhage associated with different oral anticoagulants

Neurology ◽

10.1212/wnl.0000000000003886 ◽

2017 ◽

Vol 88 (18) ◽

pp. 1693-1700 ◽

Cited By ~ 77

Author(s):

Duncan Wilson ◽

David J. Seiffge ◽

Christopher Traenka ◽

Ghazala Basir ◽

Jan C. Purrucker ◽

...

Keyword(s):

Intracerebral Hemorrhage ◽

Functional Outcome ◽

Scale Score ◽

Vitamin K ◽

Pooled Analysis ◽

Vitamin K Antagonist ◽

Cox Proportional Hazards Model ◽

Hematoma Expansion ◽

All Cause Mortality ◽

International Collaborative

Objective:In an international collaborative multicenter pooled analysis, we compared mortality, functional outcome, intracerebral hemorrhage (ICH) volume, and hematoma expansion (HE) between non–vitamin K antagonist oral anticoagulation–related ICH (NOAC-ICH) and vitamin K antagonist–associated ICH (VKA-ICH).Methods:We compared all-cause mortality within 90 days for NOAC-ICH and VKA-ICH using a Cox proportional hazards model adjusted for age; sex; baseline Glasgow Coma Scale score, ICH location, and log volume; intraventricular hemorrhage volume; and intracranial surgery. We addressed heterogeneity using a shared frailty term. Good functional outcome was defined as discharge modified Rankin Scale score ≤2 and investigated in multivariable logistic regression. ICH volume was measured by ABC/2 or a semiautomated planimetric method. HE was defined as an ICH volume increase >33% or >6 mL from baseline within 72 hours.Results:We included 500 patients (97 NOAC-ICH and 403 VKA-ICH). Median baseline ICH volume was 14.4 mL (interquartile range [IQR] 3.6–38.4) for NOAC-ICH vs 10.6 mL (IQR 4.0–27.9) for VKA-ICH (p = 0.78). We did not find any difference between NOAC-ICH and VKA-ICH for all-cause mortality within 90 days (33% for NOAC-ICH vs 31% for VKA-ICH [p = 0.64]; adjusted Cox hazard ratio (for NOAC-ICH vs VKA-ICH) 0.93 [95% confidence interval (CI) 0.52–1.64] [p = 0.79]), the rate of HE (NOAC-ICH n = 29/48 [40%] vs VKA-ICH n = 93/140 [34%] [p = 0.45]), or functional outcome at hospital discharge (NOAC-ICH vs VKA-ICH odds ratio 0.47; 95% CI 0.18–1.19 [p = 0.11]).Conclusions:In our international collaborative multicenter pooled analysis, baseline ICH volume, hematoma expansion, 90-day mortality, and functional outcome were similar following NOAC-ICH and VKA-ICH.

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Abstract 15090: Direct Oral Anticoagulation vs Vitamin K Antagonist in Atrial Fibrillation With Liver Disease: A Systematic Review and Meta-analysis

Circulation ◽

10.1161/circ.142.suppl_3.15090 ◽

2020 ◽

Vol 142 (Suppl_3) ◽

Author(s):

Mahmoud El Iskandarani ◽

Islam Shatla ◽

Muhammad Khalid ◽

Bara El Kurdi ◽

Timir Paul ◽

...

Keyword(s):

Atrial Fibrillation ◽

Systematic Review ◽

Ischemic Stroke ◽

Liver Disease ◽

Vitamin K ◽

Major Bleeding ◽

Lower Risk ◽

Meta Analysis ◽

Vitamin K Antagonist ◽

All Cause Mortality

Background: Current guidelines recommend against the use of direct oral anticoagulation (DOAC) therapy in patients with atrial fibrillation (AF) in the setting of significant liver disease (LD) due to lack of evidence in safety and efficacy studies. However, recently studies have investigated the role of DOAC in comparison to Vitamin K antagonist (VKA) in this category of patients. Therefore, we conducted a systematic review and meta-analysis to evaluate the efficacy and safety of this approach. Hypothesis: DOAC is safe and effective compared to VKA in AF with LD patients. Method: Unrestricted search of the PubMed, EMBASE, and Cochrane databases performed from inception until June 1, 2020 for studies comparing DOAC with VKA including more than 100 AF patients with LD. Relevant data were extracted and analyzed using Revman 5.3 software. Hazard ratio (HR) and 95% Confidence interval (CI) were calculated using the random-effects model. Result: A total of 5 studies (3 retrospective and 2 post hoc analysis) were included examining 39,064 patients with AF and LD (25,398 DOAC vs 13,669 VKA). DOAC is associated with lower risk of major bleeding compared to VKA with a HR of 0.68 (95% CI 0.47-0.98; I 2 =53%), all-cause mortality (HR 0.74;95% CI 0.59-0.94; I 2 =61%), and intracranial bleeding (HR 0.48; 95% CI 0.40-0.58; I 2 =0). There was no significant difference in ischemic stroke risk (HR 0.73; 95% CI 0.47-1.14; I 2 =72%) and gastrointestinal bleeding risk (0.96; 95% CI 0.61-1.51; I 2 =41%) between DOAC and VKA. Conclusion: DOAC is non-inferior to VKA regarding ischemic stroke prevention in AF patients with LD. Moreover, DOAC is associated with a lower risk of major bleeding, intracranial bleeding and all-cause mortality. Further randomized trials are needed to validate our findings.

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DICOUMAROL STUDIES: I. ORAL ADMINISTRATION OF SYNTHETIC DICOUMAROL TO VARIOUS CLASSES OF SHEEP AND CATTLE

Canadian Journal of Animal Science ◽

10.4141/cjas63-048 ◽

1963 ◽

Vol 43 (2) ◽

pp. 344-352 ◽

Cited By ~ 5

Author(s):

J. H. Linton ◽

B. P. Goplen ◽

J. M. Bell ◽

L. B. Jaques

Keyword(s):

Vitamin K ◽

Blood Clotting ◽

Post Partum ◽

Late Pregnancy ◽

Cumulative Effects ◽

Factor Vii ◽

Factor X ◽

Clotting Time ◽

Sodium Bisulphite ◽

Bull Calves

In one experiment 3 steers, 4 bull calves and 4 wether lambs were orally administered 2 milligrams dicoumarol per kilogram body weight and blood-clotting time measurements were made over a 4-day period. All animals responded to the dicoumarol but differences were evident between sheep and cattle; sheep were apparently more tolerant of the drug.The ’one-stage prothrombin’ test was more reliable and sensitive than the clotting tests employed for factor VII, factor X and prothrombin concentration.In a second experiment, 16 ewes in late pregnancy were fed rations containing 0 to 30 p.p.m. of synthetic dicoumarol and vitamin K3 as a cross treatment. Evidence of abnormal clotting power of ewe blood was observed in ewes fed diets containing 10 p.p.m. of dicoumarol. There was some indication of cumulative effects at this level after 32 days on test. At intake levels of 20 and 30 p.p.m. clotting times were affected more markedly and some ewes exhibited extended bleeding times after 2 to 4 weeks on test. No unusual hemorrhaging occurred at parturition. In general, the lambs’ blood did not reflect the pre- or post-partum dicoumarol intake of their mothers but a few lambs, as in the case of the ewes, exhibited low tolerance for dicoumarol without showing much disturbance in terms of clotting time. A large single oral dose of menadione sodium bisulphite demonstrated the effectiveness of vitamin K3 as an antidote. However, vitamin K3 as a ration supplement at 12 milligrams per pound feed failed to protect ewes against the effects of dicoumarol.

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Non-vitamin K antagonist oral anticoagulants vs. vitamin-K antagonists in patients with atrial fibrillation and chronic kidney disease: a nationwide cohort study

Thrombosis Journal ◽

10.1186/s12959-019-0211-y ◽

2019 ◽

Vol 17 (1) ◽

Cited By ~ 2

Author(s):

Emma Kirstine Laugesen ◽

Laila Staerk ◽

Nicholas Carlson ◽

Anne-Lise Kamper ◽

Jonas Bjerring Olesen ◽

...

Keyword(s):

Atrial Fibrillation ◽

Chronic Kidney Disease ◽

Kidney Disease ◽

Vitamin K ◽

Major Bleeding ◽

Vitamin K Antagonists ◽

Oral Anticoagulants ◽

Vitamin K Antagonist ◽

All Cause Mortality ◽

Comparable Population

Abstract Background We aimed to compare effectiveness and safety of non-vitamin K antagonist oral anticoagulants (NOACs) versus vitamin-K antagonists (VKA) in atrial fibrillation (AF) patients with chronic kidney disease (CKD) not receiving dialysis. Methods By using personal identification numbers, we cross-linked individual-level data from Danish administrative registries. We identified every citizen with a prior diagnosis of AF and CKD who initiated NOAC or VKA (2011–2017). An external analysis of 727 AF patients with CKD (no dialysis) was performed to demonstrate level of kidney function in a comparable population. Study outcomes included incidents of stroke/thromboembolisms (TEs), major bleedings, myocardial infarctions (MIs), and all-cause mortality. We used Cox proportional hazards models to determine associations between oral anticoagulant treatment and outcomes. Results Of 1560 patients included, 1008 (64.6%) initiated VKA and 552 (35.4%) initiated NOAC. In a comparable population we found that 95.3% of the patients had an estimated glomerular filtration rate (eGFR) < 59 mL/min. Patients treated with NOAC had a significantly decreased risk of major bleeding (hazard ratio (HR): 0.47, 95% confidence interval (CI): 0.26–0.84) compared to VKA. There was not found a significant association between type of anticoagulant and risk of stroke/TE (HR: 0.83, 95% CI: 0.39–1.78), MI (HR: 0.45, 95% CI: 0.18–1.11), or all-cause mortality (HR: 0.99, 95% CI: 0.77–1.26). Conclusion NOAC was associated with a lower risk of major bleeding in patients with AF and CKD compared to VKA. No difference was found in risk of stroke/TE, MI, and all-cause mortality.

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Reduction of salivary tissue factor (thromboplastin) activity by warfarin therapy

Blood ◽

10.1182/blood.v53.3.366.366 ◽

1979 ◽

Vol 53 (3) ◽

pp. 366-374 ◽

Cited By ~ 1

Author(s):

LR Zacharski ◽

R Rosenstein

Keyword(s):

Tissue Factor ◽

Vitamin K ◽

Coagulation Factors ◽

Human Saliva ◽

Factor Vii ◽

Clotting Factor ◽

Activate Factor ◽

Total Protein Content ◽

Factor X ◽

Clotting Factors

Abstract The coagulant of normal human saliva has been identified as tissue factor (thromboplastin, TF) by virtue of its ability to cause rapid coagulation in plasmas deficient in first-stage coagulation factors and to activate factor x in the presence of factor VII and by virtue of the fact that its activity is expressed only in the presence of factor VII and is inhibited by an antibody to TF. The TF is related to cells and cell fragments in saliva. Salivary TF activity has been found to be significantly reduced in patients taking warfarin. The decline in TF activity during induction of warfarin anticoagulation occurs during the warfarin-induced decline in vitamin-K-dependent clotting factor activity, as judged by the prothrombin time. The decrease in TF activity is not related to a reduction in salivary cell count or total protein content or to a direct effect of warfarin on the assay. It is hypothesized that the mechanism by which warfarin inhibits TF activity may be related to the mechanism by which it inhibits expression of the activity of the vitamin-K-dependent clotting factors. Inhibition of the TF activity may be involved in the antithrombotic effect of warfarin.

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The Rivaroxaban Program and the Management of Unmet Needs in Thromboembolic Disease

Thrombosis and Haemostasis ◽

10.1055/s-0038-1632387 ◽

2018 ◽

Vol 118 (S 01) ◽

pp. S2-S11

Author(s):

A. Camm

Keyword(s):

Potential Role ◽

Unmet Needs ◽

Antiplatelet Agent ◽

Factor Xa ◽

Vitamin K Antagonist ◽

Thromboembolic Disease ◽

Coagulation Cascade ◽

Vascular Protection ◽

Randomized Controlled

AbstractRivaroxaban is a non-vitamin K antagonist oral anticoagulant that acts as a direct factor Xa inhibitor, and is widely used for the prevention and treatment of thromboembolic disorders. As further knowledge gaps are identified in thrombosis management, the rivaroxaban research program has expanded in an attempt to elucidate the wider benefits of rivaroxaban. An increased understanding of the interactions taking place within the coagulation cascade may support a broader role for rivaroxaban (2.5 mg twice daily [bid] or 5 mg bid) in the setting of vascular protection, either alone or in combination with an antiplatelet agent. The aim of this article is to describe the potential role of rivaroxaban in the context of vascular protection and provide an overview of recently completed and ongoing randomized controlled trials of rivaroxaban in the areas of stroke prevention, venous protection and vascular protection.

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The host response to infection in the critically ill

10.1093/med/9780199600830.003.0303 ◽

2016 ◽

Author(s):

W. Joost Wiersinga ◽

Tom van der Poll

Keyword(s):

Critically Ill ◽

Host Response ◽

Inflammatory Responses ◽

Coagulation Cascade ◽

Microbial Infection ◽

Pathogen Invasion ◽

New Therapeutic Approaches ◽

Microbial Invasion ◽

Molecular Patterns

Infection continues to be a leading cause of intensive care unit death. The host response to infection can be seen as a pattern recognition receptor (PRR)-mediated dysregulation of the immune system following pathogen invasion in which a careful balance between inflammatory and anti-inflammatory responses is vital. A measured and rapid response to microbial invasion is essential to health. The same immunological and coagulation systems that protect against localized infection can act to our disadvantage when these systems are activated systemically during generalized microbial infection. Toll-like receptors (TLR), the inflammasomes and other PRRs initiate the host response after recognition of pathogen-associated-molecular-patterns (PAMPs) or endogenous danger-associated-molecular-patterns (DAMPs). The systemic host response to infection will result in activation of coagulation, downregulation of physiological anticoagulant mechanisms, and inhibition of fibrinolysis. Further dissection of the role of host–pathogen interactions, the cytokine response, the coagulation cascade and their multidirectional interactions in sepsis should lead towards the development of new therapeutic approaches in the critically ill who are faced with infection.

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MECHANISM OF ACTIVATION OF BLOOD COAGULATION BY LEUKOCYTE PROCOAGULANT ACTIVITY

10.1055/s-0038-1643161 ◽

1987 ◽

Author(s):

N Narahara ◽

H Sadakata ◽

T Uchiyama ◽

K Andoh ◽

H Tanaka ◽

...

Keyword(s):

Blood Coagulation ◽

Calf Serum ◽

Leukemia Cell ◽

Specific Radioactivity ◽

Activation Mechanism ◽

Leukemia Cell Line ◽

Coagulation Cascade ◽

Factor Vii ◽

Factor X ◽

Viii And Ix

To investigate the process of activation mechanism of blood coagulation by leukocytes, binding of radiolabelled Factor X and the activation of Factor X on the cell surface of leukocytes were studied by using cultured leukemia cell line, Molt-4 cells. Cells were cultured in RPMI 1640 medium with 10% inactivated fetal, calf serum at a concentration of 1x106cells/ml. After 6 hours' stimulation with 1 ug/ml of endotoxin(LPS: Escherichia coli 026:B6), cells were separated by centrifugation, washed three times with Tris containing NaCl buffer(pH 7.5, TBS), and then suspended in TBS containing 0.5% bovine serum albumin(TBS-BSA) to the concentration of 5x106 cells/ml. Factors X, VII and IX were purified from fresh-frozen human plasma by the method of Bajaj in a modified version. Factor VIII was purified from cryoprecipitate as starting material. Factor X labelled with 1-125 by the method of McFarlane showed a single band on autoradiography. Specific radioactivity was 0.3 mCi/mg. For the study on binding of Factor X, TBS-BSA solution containing 4 mM of CaClp, various amounts of radiolabelled Factor X with/without purified Factors VII, VIII and IX were added to the LPS-stimulated washed cell suspension and mixed well. N-butyl-phtalate was layered over the reaction mixture after incubation at room temperature for various minutes. Total amount of bound Factor X was calculated from the radioactivity of the cell pellet separated by centrifugation of the reaction mixture. The Xa activity generated in the supernatants was assayed using S2222.Results: Factor X bound specifically to the LPS-stimulated Molt-4 cells. Amount of bound Factor X and the dissociation constant was 1.0 ng/5x10bcells (5.2x103sites/cell) and 5x106M, respectively. More amounts of Factor X bound when Factors VIII and IX were present in the reaction mixture than their absence. Five times more Factor Xa was generated when Factors VII, VIII and IX were present in the reaction mixture as compared with presence of Factor VII, alone. These results suggest that blood coagulation cascade proceeds on the LPS-stimulated leukocyte surface.

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Role of vitamin K-dependent proteins in the arterial vessel wall

Hämostaseologie ◽

10.5482/ha-1157 ◽

2011 ◽

Vol 31 (04) ◽

pp. 251-257 ◽

Cited By ~ 22

Author(s):

M. L. L. Chatrou ◽

C. P. Reutelingsperger ◽

L. J. Schurgers

Keyword(s):

Vascular Calcification ◽

Vitamin K ◽

Independent Predictor ◽

Vitamin K Antagonists ◽

Venous Blood ◽

Coagulation Factors ◽

Coagulation Cascade ◽

High Intake ◽

Smooth Muscle Cell Migration

SummaryVitamin K was discovered early last century at the same time as the vitamin K-antagonists. For many years the role of vitamin K was solely ascribed to coagulation and coagulation was thought to be involved only at the venous blood side. This view has dramatically changed with the discovery of vitamin K-dependent proteins outside the coagulation cascade and the role of coagulation factors at the arterial side. Vitamin K-dependent proteins are involved in the regulation of vascular smooth muscle cell migration, apoptosis, and calcification. Vascular calcification has become an important independent predictor of cardiovascular disease. Vitamin K-antagonists induce inactivity of inhibitors of vascular calcification, leading to accelerated calcification. The involvement of vitamin K-dependent proteins such as MGP in vascular calcification make that calcification is amendable for intervention with high intake of vitamin K. This review focuses on the effect of vitamin K-dependent proteins in vascular disease.

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