Levels Of Procoagulant Factors Research Articles

Levels of procoagulant factors and peak thrombin generation in relation to dementia risk in older adults: The Cardiovascular Health Study

IntroductionMarkers of hemostasis such as procoagulant factors and peak thrombin generation are associated with cardiovascular outcomes, but their associations with dementia risk are unclear. We aimed to evaluate prospective associations of selected procoagulant factors and peak thrombin generation with dementia risk. MethodsWe measured levels of 7 hemostatic factors (fibrinogen, factor VII coagulant activity [FVIIc], activated factor VII [FVIIa], factor VIIa-antithrombin [FVIIa-AT], factor XI antigen [FXI], peak thrombin generation, and platelet count) among participants in the Cardiovascular Health Study, a cohort of older adults free of dementia in 1992/1993 (n = 3185). Dementia was adjudicated and classified by DSM-IV criteria through 1998/1999. Cox proportional hazards models estimated hazard ratios (HRs) for any dementia associated with 1-standard deviation (SD) differences, adjusting for sociodemographic and clinical factors and APOE genotype. Secondary analyses separately evaluated the risk of vascular dementia, Alzheimer's disease, and mixed dementia. ResultsAt baseline, participants had a median age of 73 years. Over 5.4 years of follow-up, we identified 448 dementia cases. There was no evidence of linear associations between levels of these hemostatic factors with any dementia risk (HRs per 1-SD difference ranged from 1.0 to 1.1; 95 % confidence intervals included 1.0). Results of secondary analyses by dementia subtype were similar. ConclusionsIn this prospective study, there was no strong evidence of linear associations between levels of fibrinogen, FVIIc, FVIIa, FVIIa-AT, FXI, peak thrombin generation, or platelet count with dementia risk. Despite their associations with cardiovascular disease, higher levels of these biomarkers measured among older adults may not reflect dementia risk.

Impact of TTP on COVID-19 Patients Assessing Treatment Outcomes and Healthcare Expenditure

Background: Thrombotic thrombocytopenic purpura (TTP) is a rare and life-threatening thrombotic microangiopathy manifesting as hemolytic anemia, thrombocytopenia, fever, neurological symptoms, and renal failure triggered by the immune response leading to reduced levels of ADAMTS-13. We conducted a retrospective study on a national scale utilizing the National Inpatient Sample (NIS) database for year 2020 assessing the influence of COVID-19-induced thrombotic thrombocytopenic purpura (TTP) on morbidity and mortality. Our research focused on adults aged 18 and above who had contracted COVID-19, with the aim of investigating the effects of TTP on mortality rates, cardiovascular complications, and healthcare expenditures within our patient population. Results: Our study included 1,050,045 adult patients admitted with COVID-19. Of these, only 435 (0.0004%) patients developed TTP during the index hospitalization. Patients with TTP were relatively younger than those without (61.09 vs. 64.74, p = 0.03) (Table 1). Compared to patients without TTP, patients with TTP were more likely to have congestive heart failure (CHF) (26.44% vs. 16.81%, p = 0.03), ESRD (6.90% vs. 3.68%, p = 0.04), and were more often admitted to teaching hospitals (86.21% vs. 68.95%, p = 0.02) in the Midwest (51.27% vs. 23.28%, p = 0.01) and West (20.69% vs. 17.19%, p = 0.01) regions. Using multivariate regression analysis to adjust for confounders, including the severity of COVID infection (ARF, sepsis, and organ failure), we found that COVID patients with TTP had significantly higher mortality than patients without TTP (adjusted odds ratio (AOR) 3.39, 95% CI 1.85-6.22, p < 0.01) (Table 2). Additionally, COVID patients with TTP had higher odds of LE DVT/PE (AOR 3.89, 95% CI 1.52-9.93, p < 0.01), AKI (AOR 3.67, 95% CI 1.71-7.87, p < 0.01), AKI requiring dialysis (AOR 10.68, 95% CI 4.86-23.44, p < 0.01), GIB (AOR 3.66, 95% CI 1.70-7.87, p < 0.01), requiring blood transfusion (AOR 6.65, 95% CI 3.19-13.85, p < 0.01), and ICU admission (AOR 3.81, 95% CI 2.15-6.71, p < 0.01). In terms of resource utilization, patients with TTP had a longer adjusted LOS (9.45 days, 95% CI 6.49-12.42, p < 0.01) and higher adjusted total hospitalization charges ($179,916,95% CI −86,141-273,691, p < 0.01). Conclusion: COVID-19 has been associated with TMAs, including TTP. The underlying pathophysiology includes cytokine-mediated endothelial damage and increased levels of pro-coagulant factors, such as factor VIII, vWF, and fibrinogen. Our study found that COVID-19 with concomitant TTP had a threefold higher mortality rate compared to those without TTP. Additionally, patients with TTP had a three to fourfold increased risk of LE DVT/PE, AKI, GIB, and admission to the ICU compared to patients without TTP. The presence of TTP in COVID-19 patients was also associated with longer hospital stays and higher hospitalization charges. To summarize, our study revealed that the presence of TTP in patients with COVID-19 is linked to higher mortality and an increased occurrence of complications including DVT, PE, AKI and GIB. These complications are likely the result of thrombotic events associated with TTP. Further large scale studies are warranted.

Abacavir use is associated with increased prothrombin conversion.

There is ongoing debate as to whether abacavir (ABC) increases the risk for cardiovascular disease(CVD) in people living with HIV (PLHIV) and the mechanisms underlying this possible association. We recently showed that the use of an ABC-containing regimen was independently associated with increased thrombin generation (TG). In the present study, we aim to explore these findings further, by studying the mechanistical processes that underly the global thrombin generation test via thrombin dynamics analysis. Thrombin dynamics analysis can pinpoint the cause of increased thrombin generation associated with ABC-use either to the procoagulant prothrombin conversion pathway or the anticoagulant thrombin inactivation pathway. In this cross-sectional study, 208 virally suppressed PLHIV were included, of whom 94 were on a ABC-containing regimen, 92 on a tenofovir disoproxil fumarate (TDF)-containing regimen, and the remainder on other regimens. We used Calibrated Automated Thrombinography to measure thrombin generation and perform thrombin dynamics analysis. The total amount of prothrombin conversion, as well as the maximum rate of prothrombin conversion were significantly increased in PLHIV on an ABC containing regimen compared to other treatment regimens. The levels of pro- and anticoagulant factors were comparable, indicating that the ABC-induced changes affect the kinetics of prothrombin conversion rather than procoagulant factor levels. Moreover, Von Willebrand Factor (VWF), active VWF and VWF pro-peptide levels were significantly higher in PLHIV than controls without HIV. However, they did not differ between ABC and non-ABC treated participants.

Procoagulant factors and future risk of arterial cardiovascular disease in patients with prior venous thrombosis: A cohort study.

Patients with venous thrombosis (VT) are at increased risk of future arterial cardiovascular disease (CVD) (i.e., myocardial infarction, ischemic stroke or peripheral artery disease). We investigated whether shared risk factors for VT and CVD are associated with the levels of procoagulant factors (fibrinogen, factor VIII, and von Willebrand factor), and whether the relationship between these risk factors and subsequent CVD was mediated through these procoagulant factors in patients with VT. In a follow-up study consisting of 4956 patients with VT, 2176 patients (44%) provided blood samples and were linked to the Dutch Hospital registry of Statistics Netherlands to identify hospital admissions or procedures for subsequent CVD. In total, 52 CVD events occurred over a follow-up of 11,124 years, with an incidence rate of 4.7 per 1000 patient years (95% confidence intervals 3.5-6.1). Increasing age, male sex, smoking history, major illnesses, dyslipidemia, and impaired fasting glucose levels were associated with increased CVD risk. Procoagulant factor levels were also associated with CVD risk. When adjusted for these procoagulant factors, the association between the risk factors and CVD attenuated partially. This study provides evidence that procoagulant factors can partially explain the association between increased risks of subsequent CVD in patients with previous VT.

EVALUATION OF CLOTTING FACTORS IN HOSPITALIZED CRITICALLY-ILL INDIVIDUALS WITH SUSPECTED COVID-19

The Coronavirus Disease 2019 (COVID-19), that results of Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) infection, manifests with dysfunction of hemostasis and thrombosis. This study aims to evaluate laboratory parameters of hemostasis in hospitalized individuals with suspected COVID-19. Individuals aged 18 years or older with suspected COVID-19 admitted to two hospitals were invited to participate in this study. The study inclusion period was from April 2020 to March 2021. The study was approved by the institutional ethics committees. The diagnosis of COVID-19 was confirmed by positive SARS-CoV-2 real-time reverse-transcription polymerase chain reaction. Antithrombin, factor V, factor VII, factor XI, factor XII, factor XIII and prothrombin assays were performed using the Multiplex immunoassay technique (ThermoFisher Scientific, Vienna, Austria). Propensity score matching for sex and age were estimated by a logistic regression model for COVID-19 and non-COVID-19 individuals in the R software. The proportions found in each group were compared by Fisher's exact test, when the variable was categorical, and by the Mann-Whitney test, when it was continuous. Linear regression was performed adjusting the levels of clotting factors and antithrombin for the severity score (Sequential Organ Failure Assessment - SOFA). Correlation between SOFA, clotting factors and antithrombin in individuals with COVID-19 were performed by using the Spearman test. Only very strong correlations (≥0.9) were considered; p-value<0.05 was considered statistically significant. A total of 151 individuals were included in the study, of whom 138 (91.4%) with the diagnosis of COVID-19 and 13 (8.6%) non-COVID-19. After 2:1 matching, 26 individuals with COVID-19 and 13 non-COVID-19 participated in the study. In the univariate analysis, the group of COVID-19 had higher levels of antithrombin, factor V, factor VII, factor XI and prothrombin compared to the non-COVID-19 group. However, after adjusting for SOFA, only the levels of factor XI and prothrombin remained different between the groups (higher in the COVID-19) (p=0.04 and p=0.04, respectively). We found no association between factor XI and prothrombin with mortality. However, we found a very strong correlation between coagulation factors V and VII (r=0.923, p<0.0001). Our results show that plasma levels of antithrombin, factor V, factor VII, factor XI and prothrombin were higher in the COVID-19 when compared with non-COVID-19 group of critically-ill patients, but the difference was lost after adjusting the analysis for SOFA. Only the levels of factor XI and prothrombin remained significant in the COVID-19 group after adjustment. This finding suggests that the severity of the disease rather than viral etiology was the main determinant of the difference in the plasma levels of these proteins. We also showed a strong correlation between factor V and VII in our study. Indeed, factor VII is the major trigger of coagulation in vivo . Therefore, it is possible that factor V and VII could act together to boost coagulation and promote thrombus formation in patients with COVID-19. Our study suggests that increased levels of procoagulant factors in hospitalized critically-ill individuals with suspected COVID-19 are rather related to disease severity than to its cause.

Lower-leg injury and knee arthroscopy have distinct effects on coagulation

AbstractIt is unknown how lower-leg injury and knee arthroscopy, both associated with venous thromboembolism (VTE), affect coagulation. To study the effect of (1) lower-leg trauma and (2) knee arthroscopy on coagulation, plasma samples of the Prevention of Thrombosis following CAST immobilization (POT-CAST, #NCT01542762) and Prevention of Thrombosis following Knee Arthroscopy (POT-KAST, #NCT01542723) trials were used, which were collected shortly after lower-leg trauma and before/after (<4 hours) knee arthroscopy. For aim 1, 1204 lower-leg injury patients were compared with preoperative samples of 1001 controls. Mean differences/ratios (if ln-retransformed because of skewedness) were adjusted for sex, age, body mass index, comorbidity, malignancy, and oral contraceptives using linear regression. For aim 2, perioperative mean changes of 715 arthroscopy patients were calculated. Plasma levels of fibrinogen, factor (F)VIII, FIX, FXI, von Willebrand Factor (VWF), and D-dimer were measured in all individuals. Parameters of underlying mechanisms (tissue factor, interleukin-6 [IL-6], myeloperoxidase DNA, cell-free DNA) were measured in random subsets. In lower-leg injury patients, coagulation parameter levels increased, especially FVIII, VWF, and D-dimer, that is, adjusted mean differences: FVIII 26.8% (95% confidence interval [CI], 23.7-29.9), FIX 13.8% (95% CI, 11.9-15.6), FXI 5.1% (95% CI, 3.3-7.0), VWF 29.8% (95% CI, 26.0-33.6), fibrinogen 32.5 mg/dL (95% CI, 25.8-39.2), and D-dimer (mean ratio) 3.3 (95% CI, 3.1-3.6). Remaining parameters were unchanged, except for increased IL-6 levels. After arthroscopy, all parameters decreased. Lower-leg trauma is associated with increased procoagulant factor levels in contrast to knee arthroscopy. This suggests that, in both situations, different pathways are involved in development of VTE.

Sex Differences in Hemostatic Factors in Patients With Ischemic Stroke and the Relation With Migraine-A Systematic Review.

Background: Women are more affected by stroke than men. This might, in part, be explained by sex differences in stroke pathophysiology. The hemostasis system is influenced by sex hormones and associated with female risk factors for stroke, such as migraine.Aim: To systematically review possible sex differences in hemostatic related factors in patients with ischemic stroke in general, and the influence of migraine on these factors in women with ischemic stroke.Results: We included 24 studies with data on sex differences of hemostatic factors in 7247 patients with ischemic stroke (mean age 57–72 years, 27–57% women) and 25 hemostatic related factors. Levels of several factors were higher in women compared with men; FVII:C (116% ± 30% vs. 104% ± 30%), FXI (0.14 UI/mL higher in women), PAI-1 (125.35 ± 49.37 vs. 96.67 ± 38.90 ng/mL), D-dimer (1.25 ± 0.31 vs. 0.95 ± 0.24 μg/mL), and aPS (18.7% vs. 12.0% positive). In contrast, protein-S (86.2% ± 23.0% vs. 104.7% ± 19.8% antigen) and P-selectin (48.9 ± 14.4 vs. 79.1 ± 66.7 pg/mL) were higher in men. Most factors were investigated in single studies, at different time points after stroke, and in different stroke subtypes. Only one small study reported data on migraine and hemostatic factors in women with ischemic stroke. No differences in fibrinogen, D-dimer, t-PA, and PAI-1 levels were found between women with and without migraine.Conclusion: Our systematic review suggests that sex differences exist in the activation of the hemostatic system in ischemic stroke. Women seem to lean more toward increased levels of procoagulant factors whereas men exhibit increased levels of coagulation inhibitors. To obtain better insight in sex-related differences in hemostatic factors, additional studies are needed to confirm these findings with special attention for different stroke phases, stroke subtypes, and not in the least women specific risk factors, such as migraine.

Thromboembolic disease in hypercortisolism.

Endogenous Cushing's syndrome (CS) is associated with increased patient morbidity (hypertension, diabetes mellitus, dyslipidemia, visceral obesity, osteoporosis, cognitive alterations, and impaired quality of life). Both arterial and venous thromboembolic events (TE) due to alterations in the hemostatic system and prothrombotic state are widely reported in patients with CS, more so postoperatively. Increased mortality, if not appropriately treated, is largely due to cardiovascular events and infections. Patients with CS have markedly increased risk of thromboembolic episodes compared to the general population. The prothrombotic state is mediated by increased levels of procoagulant factors, but also by an impaired fibrinolytic capacity. All contribute to TE, atherosclerosis, and subsequent cardiovascular morbidity and mortality. Some abnormalities progressively improve after CS remission, but do not fully normalize for at least 1 year or more. Due to the additional thrombotic risk of surgery or any invasive procedure, anticoagulation prophylaxis should be at least considered in patients with CS and balanced with individual bleeding risk. However, a clear protocol of thromboprophylaxis is lacking and increased awareness regarding risks per se is needed. Large prospective trials will clarify, which patients with CS are at the highest risk and the optimal prevention protocol to minimize risks and maximize efficacy.

Procoagulant factor levels and risk of venous thrombosis in the elderly

Unlabelled Box AbstractBackgroundVenous thrombosis (VT) incidence increases markedly with age. Coagulation factors are also positively associated with age. ObjectiveTo study whether higher levels of coagulation factors II (prothrombin), VIII, IX, and XI are associated with risk of a first VT in the elderly. MethodsFour hundred and one patients and 431 control subjects aged 70 and older were included in the Age and Thrombosis, Acquired and Genetic risk factors in the Elderly (AT‐AGE) study. Blood was collected 1 year after the event in patients and in all control subjects for measurement of coagulation factors. To assess the risk of VT, odds ratios (ORs) were calculated after stratification of coagulation factors in quartiles and at the 90th percentile, adjusting for potential confounders (age, sex, body mass index, and study center). ResultsMean age was 78 years (range: 70‐100 years). The ORs of VT for factors in the top quartile compared with the lowest quartile were 4.5 (95% confidence interval [CI]:2.7‐7.3) for factor VIII, 2.4 (95% CI:1.1‐5.2) for factor IX, and 1.7 (95% CI:1.0‐2.9) for factor XI. High prothrombin was not associated with an increased VT risk. There was no dose‐response association between the number of high coagulation factors and VT risk. The population attributable risk (PAR) of VT was 37.6%, 23.3%, and 12.4% for factor VIII, IX, and XI, respectively. ConclusionIn this study of the elderly, higher factors VIII, IX, and XI but not prothrombin, were positively associated with the risk of VT.

Oral Contraceptives and Venous Thromboembolism: Focus on Testing that May Enable Prediction and Assessment of the Risk

Combined oral contraceptives (COCs) induce several changes in the levels of coagulation factors. The levels of procoagulant factors are often increased, while levels of anticoagulant factors are decreased. Fibrinolysis is also affected, even if the effect seems to be more counterbalanced by opposite regulation of profibrinolytic and antifibrinolytic factors. These effects on hemostasis are more pronounced with third- or fourth-generation COC compared with second-generation COC. Venous thromboembolism (VTE) risk increases when multiple risk factors, including genetic and environmental, are present simultaneously. COC use causes changes in coagulation that modify the prothrombotic state induced by preexisting hemostatic alterations in a supra-additive manner. Therefore, testing appears to be of importance not only before implementing COC but also to monitor any potential thrombogenicity induced by COC therapy. Inherited genetic factors, such as factor V Leiden, G20210A prothrombin mutation, antithrombin, protein C or protein S deficiencies, non-O blood group, as well as CYP2C9*2 and the rs4379368 mutations, have all been identified as genetic predictive risk factors of VTE in women. Nevertheless, the screening of these genetic biomarkers is not capable of assessing the phenotypic expression of the risk. This review will focus on the different options for screening the thrombogenic status in this population. Specific attention will be given to the endogenous thrombin potential-based activated protein C resistance, a test aiming at assessing the thrombogenicity induced by hormonal therapies and inherited or acquired thrombophilia.

Thromboinflammation and the hypercoagulability of COVID‐19

The pathogenic coronavirus has been wreaking havoc worldwide since January. Infection with SARS‐CoV‐2 is problematic as no one has prior immunity, and no specific antiviral treatments are available. While many people with COVID‐19 develop mild to moderate symptoms, some develop profound, seemingly unchecked inflammatory responses leading to acute lung injury and hypoxemic respiratory failure, the most common cause of death. The interplay between inflammation and coagulation—thromboinflammation‐‐has been well described, and recently reviewed.1.Lillicrap D. Disseminated intravascular coagulation in patients with 2019‐nCoV pneumonia.J Thromb Haemost. 2020; 18: 786-787Crossref PubMed Scopus (206) Google Scholar, 2.Jackson S.P. Darbousset R. Schoenwaelder S.M. Thromboinflammation: challenges of therapeutically targeting coagulation and other host defense mechanisms.Blood. 2019; 133: 906-918Crossref PubMed Scopus (277) Google Scholar COVID‐19 infection is associated with coagulation abnormalities characterized by increases in procoagulant factor levels including fibrinogen, and increases in D‐dimers that have been associated with higher mortality.3.Zhou F. Yu T. Du R. et al.Clinical course and risk factors for mortality of adult inpatients with COVID‐19 in Wuhan, China: a retrospective cohort study.Lancet. 2020; 395: 1054-1062Abstract Full Text Full Text PDF PubMed Scopus (15878) Google Scholar, 4.Wang D. Hu B. Hu C. et al.Clinical characteristics of 138 hospitalized patients with 2019 novel coronavirus‐infected pneumonia in Wuhan, China.JAMA. 2020; 323: 1061-1069Crossref PubMed Scopus (13852) Google Scholar While sepsis induced coagulopathy (SIC) and disseminated intravascular coagulopathy (DIC) have been documented with severe disease, especially in non‐survivors, a hyperfibrinolytic consumptive DIC with a bleeding diathesis has not been reported.5.Tang N. Li D. Wang X. Sun Z. Abnormal coagulation parameters are associated with poor prognosis in patients with novel coronavirus pneumonia.J Thromb Haemost. 2020; 18: 844-847Crossref PubMed Scopus (3429) Google Scholar, 6.Tang N. Bai H. Chen X. Gong J. Li D. Sun Z. Anticoagulant treatment is associated with decreased mortality in severe coronavirus disease 2019 patients with coagulopathy.J Thromb Haemost. 2020; 18: 1094-1099Abstract Full Text Full Text PDF PubMed Scopus (2108) Google Scholar The findings of Tang et al suggested that routine prophylactic dose heparin can decrease mortality in those with the most severe coagulation disturbances, defined as a SIC score ≥4 or D‐dimer >3.0 mg/L.6.Tang N. Bai H. Chen X. Gong J. Li D. Sun Z. Anticoagulant treatment is associated with decreased mortality in severe coronavirus disease 2019 patients with coagulopathy.J Thromb Haemost. 2020; 18: 1094-1099Abstract Full Text Full Text PDF PubMed Scopus (2108) Google Scholar, 7.Iba T. Levy J.H. Warkentin T.E. et al.Diagnosis and management of sepsis‐induced coagulopathy and disseminated intravascular coagulation.J Thromb Haemost. 2019; 17: 1989-1994Crossref PubMed Scopus (240) Google Scholar Recent published and other reports note what appears to be an increased incidence of venous thromboembolic events (VTE) in critically ill patients admitted to the intensive care unit (ICU) with COVID‐19. Klok et al reported a 27% (95% confidence interval 17‐37) VTE incidence and 3.7% arterial vascular events despite the use of standard weight based VTE prophylaxis with low molecular weight heparin (LMWH).8.Klok F.A. Kruip M.J.H.A. van der Meer N.J.M. et al.Incidence of thrombotic complications in critically ill ICU patients with COVID‐19.Thromb Res. 2020; 191: 145-147Abstract Full Text Full Text PDF PubMed Scopus (2737) Google Scholar Of note, the failure rate for standard VTE prophylaxis in an ICU setting is 7.7%.9.Lim W. Meade M. Lauzier F. et al.Failure of anticoagulant thromboprophylaxis: risk factors in medical‐surgical critically ill patients* Multicenter Study; Randomized Controlled Trial.Crit Care Med. 2015; 43: 401-410Crossref PubMed Scopus (82) Google Scholar Cui et al report a similar 25% incidence of VTE in China, but VTE prophylaxis was not given, as the incidence of VTE in Asian populations is very low, therefore VTE prophylaxis not routinely used.10.Cui S. Chen S. Li X. Liu S. Wang F. Prevalence of venous thromboembolism in patients with severe novel coronavirus pneumonia.J Thromb Haemost. 2020; 18: 1421-1424Abstract Full Text Full Text PDF PubMed Scopus (1108) Google Scholar, 11.Zakai N.A. McClure L.A. Racial differences in venous thromboembolism.J Thromb Haemost. 2011; 9: 1877-1882Crossref PubMed Scopus (163) Google Scholar In addition to increased VTE incidence, published pathology reports and verbal communications have identified both microvascular thrombosis and pulmonary emboli at autopsy in the small number of patients currently reported. The microvascular thrombosis is seen in an environment of marked inflammatory changes including mononuclear cell infiltrates, virally infected cells, and diffuse alveolar damage (https://www.medrxiv.org/content/10.1101/2020.04.06.20050575v1, accessed April 12, 2020). In this issue of the Journal of Thrombosis and Haemostasis, Rannuci and colleagues report on coagulation parameters in COVID‐19 patients including interleukin 6 levels, fibrinogen, D‐dimers, and viscoelastic testing in critically ill patients with acute respiratory distress syndrome (ARDS).12.Ranucci M. Ballotta A. Di Dedda U. et al.The procoagulant pattern of patients with COVID‐19 acute respiratory distress syndrome.J Thromb Haemost. 2020; 18: 1747-1751Abstract Full Text Full Text PDF PubMed Scopus (581) Google Scholar Baseline testing on admission in 16 patients receiving 4000 international units (IU) nadroparin twice daily included prothrombin time (PT), partial thromboplastin time (PTT), fibrinogen, D‐dimer, and viscoelastic measurements. Initial results were similar to other reports, with the median fibrinogen level elevated above the upper limit of normal. Despite normal clotting times on viscoelastic testing, other indices demonstrated increased clot firmness with above normal values for contributions from fibrinogen (94%) and platelets (62%), after which time nadroparin dosing was empirically increased to 6000 or 8000 IU BID if body mass index (BMI) > 35 kg/m2. Two patients were treated with antithrombin concentrates for levels < 70% and one patient was treated with clopidogrel 75 mg/day for a platelet count > 400 000/µL. Follow up standard coagulation test results were available for 10 patients over 7 days of the increased dose, and 9 had a second viscoelastic test after 2 weeks of increased LMWH. The use of an increased prophylactic dose of nadroparin resulted in a significant decrease in D‐dimer levels although all patients still had values above the normal range. Similarly, viscoelastic testing suggested decreased hypercoagulability after increasing LMWH as Rannucci et al show in figure 2, and decreases in clot firmness as a result of a decreased contribution from fibrinogen and platelets to varying degrees. One important finding from this report is the correlation of Il‐6 and fibrinogen levels, demonstrating and confirming the link between inflammation and pro‐coagulant changes. All patients had IL‐6 levels far above the upper limit of normal at admission. The major cause of mortality in patients with COVID‐19, progressive hypoxemic respiratory failure and ARDS, is mediated by lung injury caused by the invading pathogen. Viral infection has been demonstrated in multinucleated cells on autopsy in the alveoli of COVID‐19 infected patients.13.Xu Z. Shi L. Wang Y. et al.Pathological findings of COVID‐19 associated with acute respiratory distress syndrome.Lancet Respir Med. 2020; 8: 420-422Abstract Full Text Full Text PDF PubMed Scopus (5450) Google Scholar The primary infection initiates alveolar injury and the resulting inflammatory response, including production of inflammatory cytokines, including IL‐6, which has been demonstrated to be significantly elevated in COVID‐19 patients, as well as activation and recruitment of mononuclear cells and neutrophils causing more tissue damage, including damage to the capillary endothelium. In addition to the procoagulant effectors derived as the result of inflammation (including cytokines, neutrophil extracellular traps [NETs], polyphosphates) the usual thrombo‐protective state of the vascular endothelial cells is disrupted; both pathophysiologic changes lead to the development of microvascular thrombosis. Over time the pathology of ARDS progresses to a proliferative and then ultimately a fibrotic state, which is ultimately fatal. Rannuci et al's report suggests that an increased prophylactic LMWH dose appears to dampen the downstream thrombotic results of the marked inflammatory response to COVID‐19. Although patient improvement with viral clearance and decreased inflammatory effects may have occurred and been responsible for some of the changes, despite the decrease in D‐dimers the fibrinogen values were still elevated, and the mortality in this small number of patients with ARDS was high. Whether intervening earlier with anticoagulants before patients develop ARDS would make a difference, or whether preventing the microvascular thrombosis will change outcomes remains to be determined. Certainly, it is possible as suggested by Rannuci et al that using increased doses of LMWH might halt the progression to overt DIC as well as mitigate the contribution of microvascular thrombosis to the hypoxemic respiratory failure. For clinicians trained in using an evidence‐based medicine approach, we find ourselves forced to practice without data. Is an empiric increase in prophylactic anticoagulation dose justified with the limited data we have? Despite the small numbers reported, the use of increased LMWH dose was not associated with increased bleeding. Precedent exists in other clinical situations in which patients are considered at a high risk for VTE, for the use of an off‐label increased dose of enoxaparin 40 mg (4000 IU) or 60 mg every 12 hours based on BMI for post‐bariatric surgery patients, or in pregnancy where increased doses are advised for prophylaxis with minimal supporting data.14.Borkgren‐Okonek M.J. Hart R.W. Pantano J.E. et al.Enoxaparin thromboprophylaxis in gastric bypass patients: extended duration, dose stratification, and antifactor Xa activity.Surg Obes Relat Dis. 2008; 4: 625-631Abstract Full Text Full Text PDF PubMed Scopus (114) Google Scholar, 15.Bates S.M. Greer I.A. Middeldorp S. Veenstra D.L. Prabulos A.M. Vandvik P.O. VTE, thrombophilia, antithrombotic therapy, and pregnancy: Antithrombotic Therapy and Prevention of Thrombosis, 9th ed: American College of Chest Physicians Evidence Based Clinical Practice Guidelines. American College of Chest Physicians.Chest. 2012; 141: e691SAbstract Full Text Full Text PDF PubMed Scopus (1056) Google Scholar Some guidance documents from around the world suggest using standard coagulation test values to determine anticoagulant dosing for COVID‐19, as suggested in a French guidance document, which recommends full therapeutic dose anticoagulation for patients with increased fibrinogen > 8 g/L or D‐dimer > 3.0 µg/mL (https://www.fichier‐pdf.fr/2020/04/03/covid‐19‐gihp‐gfht‐3‐avril‐final‐3/?, accessed April 13, 2020). While Klok and colleagues reported using a standard dose of 2850 IU nadroparin daily, with 5700 IU daily for those weighing over 100 kg, the mean weight was 87 kg ± 16, with few patients weighing more than 100 kg. The Netherlands centers changed practice after a month of experience treating COVID‐19 patients; nadroparin doses were increased to 5700 IU daily regardless of weight at one center, and at another center the dose was increased to 5700 IU twice a day, very similar to the escalated dose used by Rannuci et al.8.Klok F.A. Kruip M.J.H.A. van der Meer N.J.M. et al.Incidence of thrombotic complications in critically ill ICU patients with COVID‐19.Thromb Res. 2020; 191: 145-147Abstract Full Text Full Text PDF PubMed Scopus (2737) Google Scholar, 12.Ranucci M. Ballotta A. Di Dedda U. et al.The procoagulant pattern of patients with COVID‐19 acute respiratory distress syndrome.J Thromb Haemost. 2020; 18: 1747-1751Abstract Full Text Full Text PDF PubMed Scopus (581) Google Scholar These increased doses may be required to overcome the dramatic elevation in levels of procoagulant factors such as fibrinogen, factor VIII, and others, that are not present in the standard post arthroplasty or hospitalized medically ill patient. In COVID‐19 patients, a risk adapted approach to escalating the dose of anticoagulation despite minimal supporting data should be carefully considered after assessing the bleeding risk for each patient. Monitoring fibrinogen, PT, PTT, and renal function should be performed. However, increasing anticoagulant doses alone is likely insufficient to change outcomes in patients with severe COVID‐19 acute lung injury. Additional therapy with novel anti‐inflammatory agents such as IL‐6 and Il‐1 antagonists, and other approaches to treating the cytokine storm that appears to be responsible for severe and fatal infections, may be critical to decrease the thromboinflammatory responses and subsequent tissue injury that drive the prothrombotic changes resulting in microvascular thrombosis and overt VTE. Anticoagulation might play a role by preventing the contribution of microvascular thrombosis to the progression of respiratory failure, giving time for anti‐inflammatory agents to work to decrease damage and to allow innate immunity to clear the virus. As with anticoagulation dosing, multiple anti‐inflammatory agents are being used with similar lack of data to guide care. While randomized controlled trials are the ideal, and are being developed or are under way for both anti‐inflammatory therapies and anticoagulants, the exponentially increasing numbers of infected patients and the rapid pace of the disease leave little time for many to participate in well‐conducted studies. However, the report by Rannuci et al provide important insight into the hypercoagulability and thromboinflammatory response associated with COVID‐19 and acute lung injury, and may provide some perspective on additional therapeutic strategies to decrease the morbidity and mortality associated with the disease. J. M. Connors and J. H. Levy equally contributed to the writing of this manuscript. J.M. Connors: Research funding to the institution from CSL Behring. J. H. Levy: Serves on research, data safety, or advisory committees for CSL Behring, Instrumentation Labs, Janssen, Merck, Octapharma.

Coagulation Factor Levels and Underlying Thrombin Generation Patterns in Adult Extracorporeal Membrane Oxygenation Patients.

There is a paucity of data on the underlying procoagulant-anticoagulant balance during extracorporeal membrane oxygenation (ECMO). We hypothesized that adult ECMO patients would have an imbalance between procoagulant and anticoagulant factors, leading to an abnormal underlying thrombin generation (TG) pattern. Twenty adult venoarterial (VA) ECMO patients had procoagulant and anticoagulant factor levels measured temporally on ECMO day 1 or 2, day 3, and day 5. In heparin-neutralized plasma, underlying TG patterns, and sensitivity to activated protein C were assessed using calibrated automated thrombogram. TG parameters including lag time, peak TG, and endogenous thrombin potential (ETP) were compared against 5 normal plasma controls (3 males and 2 females) obtained from a commercial supplier. Thrombomodulin (TM) was added to some samples to evaluate for activated protein C resistance. Procoagulant factors (factor [F] II, FV, and FX) were mostly in normal reference ranges and gradually increased during the first 5 ECMO days (P = .022, <.001, <.001). FVIII levels were elevated at all time points and did not change (P = .766). In contrast, FXI was in the low-normal range but did not increase during ECMO (P = .093). Antithrombin (AT) and protein C levels were below normal but increased during the first 5 ECMO days (P = .002 and P = .014). Heparinase-treated samples showed prolonged lag time, increased peak TG, and increased ETP compared to controls; mean difference in lag time on ECMO day 1 or 2 = 6.0 minutes (99% confidence interval [CI], 2.8-9.2), peak TG = 193.4 (99% CI, 122.5-264.3), and ETP = 1170.4 (99% CI, 723.2-1617.6). After in vitro TM treatment, differences in TG parameters were accentuated and ECMO samples appeared insensitive to TM treatment; mean difference in lag time on ECMO day 1 or 2 = 9.3 minutes (99% CI, 6.2-12.4), peak TG = 233.0 (99% CI, 140.9-325.1), and ETP = 1322.5 (99% CI, 764.8-1880.2). Similar differences in TG parameters were observed on ECMO days 3 and 5. Contact activation occurs during ECMO, but procoagulant factor levels are generally preserved. Although heparin-neutralized TG is delayed, peak TG and ETP are supranormal in the setting of high FVIII and low AT and protein C levels. Resistance to TM is also apparent. These changes demonstrate a possible mechanism for hypercoagulability during adult VA ECMO.

Thromboelastography Detects Possible Coagulation Disturbance in Pediatric Patients with Portal Cavernoma

Background: Thromboelastography (TEG) allows a dynamic assessment of clot formation and dissolution that might be useful for assessing the relative contribution of the coagulation components to overall clot formation and dissolution, but it has not been fully defined in patients with portal cavernoma (PC). Methods: We retrospectively recruited consecutive patients with PC between July 2006 and June 2016 who had no abdominal malignancy or liver cirrhosis. Blood samples were drawn on admission and were subjected to coagulation parameter assessment, including conventional coagulation tests, measurement of the circulating levels of procoagulant and anticoagulant factors, and TEG assessment. Results: Compared with controls, patients with PC showed significant reductions in the serum levels of procoagulant factors and anticoagulants factors, whereas factor VIII was slightly elevated. TEG showed clot formation (α-angle), and the maximal clot strength (MA) was higher in patients with PC than in controls, indicating a hypercoagulable state. Thrombocytopenia decreased both clot formation (α-angle) and the maximal clot strength (MA) but was still significantly higher than the control. Furthermore, patients with PC had a higher level of D-dimer and LY30 than did controls, indicating the in vivo activation of coagulation and fibrinolysis. Conclusion: TEG analysis showed that patients with PC were in a hypercoagulable state that could be partially masked by thrombocytopenia secondary to splenomegaly and hypersplenism in these patients, which indicates that our current prophylaxis and therapy regimen could be improved.

ABO blood group and procoagulant factors: the hypercoagulation hypothesis ABO and Procoagulant Factors.

The correlation between procoagulant levels-factor VIII (FVIII), von Willebrand factor (vWF), and fibrinogen-and risk of thrombosis has been well documented in adult populations. We hypothesize that interaction of passively transferred isoagglutinins in premature neonates with a compromised immune system may trigger an immune response that can target the immature gastrointestinal tract. The objective of this study is to evaluate if there are procoagulant level differences in preterm newborns stratified by ABO blood group. VWF, FVIII, and fibrinogen levels were analyzed in neonates ≤32 weeks and/or birthweight ≤1500 g over the first 6 weeks of life. Demographic, blood type, and transfusion data were collected. Elevations in vWF and FVIII were found to be statistically significant in the third week of life in non-O neonates vs. type O neonates. FVIII was also found to be significantly elevated in week 1. Transfused neonates also showed elevations between weeks 0 and 3. There appears to be a time-dependent variation in procoagulant factor levels in preterm newborns. Although the clinical significance remains unclear, prothrombotic factors vWF and FVIII are significantly higher in non-O blood-type preterm neonates in the third week of life.

Coagulation profile in patients with chronic liver disease

Background: Chronic liver disease (CLD) is defined as a process of slow and continuous destruction and regeneration of the hepatic parenchyma giving rise to fibrosis and cirrhosis. When it has markedly progressed, it may present with clinical bleeding due to reduction in levels of procoagulant factors, barring some like factor VIII and von Willebrand factor, which are elevated. It is essential to observe that reduced levels of the procoagulants are accompanied by decrease in levels of anticoagulants such as antithrombin and protein C. Under normal conditions, the coagulation machinery is balanced, but the phenomenon of the simultaneous reduction of procoagulants as well as anticoagulants in patients with CLD has been an unsolved puzzle since long. Objective: This study was undertaken to study the relevance and significance of first-line coagulation tests (prothrombin time [PT] and activated partial thromboplastin time [aPTT]) in relation to bleeding manifestations in patients with CLD, to classify the cases of CLD enrolled on the basis of etiology, to study the platelet count, PT, and aPTT values of the cases, and to calculate the Child–Pugh (CP) and model for end-stage liver disease (MELD) scores for all the patients and stratify them accordingly. Materials and Methods: It was a prospective observational study including 40 patients known to be diagnosed with CLD. CP score and MELD were calculated for all. Values of coagulation parameters were compared in patients with and without cirrhosis, in patients belonging to different CP classes, those with low and high MELD scores, and patients with or without upper gastrointestinal (UGI) bleed. Results: Means of PT and aPTT were compared in patients with and without cirrhosis where it was found that there was no statistically significant prolongation of PT or aPTT in patients with cirrhosis compared to those without. We also studied the values of PT and aPTT through increasing grades of CP score and found statistically significant difference between values of PT between those belonging to Class A versus Class C. It was observed that the difference of the mean of PT of the two groups (with MELD

High levels of coagulation factors and venous thrombosis risk: strongest association for factor VIII and von Willebrand factor

Essentials Elevated procoagulant levels are associated with an increased risk of venous thrombosis (VT). The dependency on concurrent increased factor levels and VT was analyzed in a large study. Factor VIII (FVIII) and von Willebrand factor (VWF) were associated with the highest VT risk. The risks for other procoagulant factor levels were largely explained by FVIII and VWF. SUMMARY: Background Coagulation factors are essential for robust clot formation. However, elevated levels of procoagulant factors are associated with an increased risk of venous thrombosis (VT). The precise contribution of these factors to the development of VT is not yet understood. Objectives We determined the thrombosis risk for the highest levels of eight selected coagulation factors. Furthermore, we analyzed which of these coagulation factors had the strongest impact on the supposed association. Methods We used data of 2377 patients with a first VT and 2940 control subjects in whom fibrinogen, von Willebrand factor (VWF), factorII, FVII, FVIII, FIX, FX and FXI levels were measured. Results The odds ratios (ORs) for the various coagulation factor levels (>99th percentile versus ≤25th percentile) varied between 1.8 and 4, except for FVIII (OR23.0; 95% confidence interval [CI]14.7-36.0) and VWF (OR24.0; 95%CI15.3-37.3). Adjustment for FVIII and VWF in a mediation analysis reduced the risks of the other factors to unity, with the exception of FIX and FXI (remaining ORs between 1.7 and 1.9). Conversely, the ORs for FVIII and VWF levels remained high after adjustment for all other procoagulant factors (FVIII: 16.0; 95%CI9.7-26.3; VWF: 17.6; 95%CI10.7-28.8). Conclusions Our results imply that the observed relationship between VT and coagulation factor levels can be largely explained by FVIII and VWF. FVIII and VWF levels were also associated with the highest VT risk.

Elevated coagulation factor levels affect the tissue factor-threshold in thrombin generation

IntroductionAltered levels of factor (F)VIII, prothrombin, or antithrombin have been associated with an increased risk for venous thromboembolism (VTE). However, the exact molecular mechanism by which these altered factor levels modulate the risk is incompletely understood. Here we hypothesize that elevated factor levels affect the pro- and anticoagulant balance in coagulation such that even minute amounts of tissue factor (TF) will initiate thrombin formation, thereby contributing to the VTE risk. Materials and methodsTo test this so-called TF-threshold hypothesis, we monitored thrombin generation initiated by very low TF concentrations in FXII-deficient plasma, to avoid any contact pathway-mediated thrombin formation. Furthermore, similar experiments were performed in the presence of increasing concentrations of pro- and anticoagulant proteins. ResultsA TF-threshold was established in the FXII-deficient plasma, which is subject to inter-individual variation. Elevated plasma levels of procoagulant factors, such as FVIII or prothrombin, enhanced thrombin generation and reduced the amount of TF required for the initiation of thrombin formation. Conversely, elevated levels of the coagulation inhibitor antithrombin increased the TF-threshold. ConclusionsOur findings support a mediating role for the TF-threshold in the association between high procoagulant factor levels and the risk for VTE. Furthermore, elevated levels of anticoagulants may have a protective effect on the development of VTE.

Tryptophan-Derived Uremic Toxins and Thrombosis in Chronic Kidney Disease.

Patients with chronic kidney disease (CKD) display an elevated risk of thrombosis. Thrombosis occurs in cardiovascular events, such as venous thromboembolism, stroke, and acute coronary syndrome, and is a cause of hemodialysis vascular access dysfunction. CKD leads to the accumulation of uremic toxins, which exerts toxic effects on blood and the vessel wall. Some uremic toxins result from tryptophan metabolization in the gut through the indolic and the kynurenine pathways. An increasing number of studies are highlighting the link between such uremic toxins and thrombosis in CKD. In this review, we describe the thrombotic mechanisms induced by tryptophan-derived uremic toxins (TDUT). These mechanisms include an increase in plasma levels of procoagulant factors, induction of platelet hyperactivity, induction of endothelial dysfunction/ impairment of endothelial healing, decrease in nitric oxide (NO) bioavailability, and production of procoagulant microparticles. We focus on one important prothrombotic mechanism: The induction of tissue factor (TF), the initiator of the extrinsic pathway of the blood coagulation. This induction occurs via a new pathway, dependent on the transcription factor Aryl hydrocarbon receptor (AhR), the receptor of TDUT in cells. A better understanding of the prothrombotic mechanisms of uremic toxins could help to find novel therapeutic targets to prevent thrombosis in CKD.

Determinants of impaired renal and vascular function are associated with elevated levels of procoagulant factors in the general population

Background Impaired renal and vascular function have been associated with venous thrombosis, but the mechanism is unclear. Objectives We investigated whether estimated glomerular filtration rate (eGFR), urinary albumin-creatinine ratio (UACR), and pulse wave velocity (PWV) are associated with a procoagulant state. Methods In this cross-sectional analysis of the NEO Study, eGFR, UACR, fibrinogen, and coagulation factors (F)VIII, FIX and FXI were determined in all participants (n=6536), and PWV was assessed in a random subset (n=2433). eGFR, UACR and PWV were analyzed continuously and per percentile: per six categories for eGFR (>50th [reference] to <1st) and UACR (<50th [reference] to >99th), and per four categories (<50th [reference] to >95th percentile) for PWV. Linear regression was used and adjusted for age, sex, total body fat, smoking, education, ethnicity, total cholesterol, C-reactive protein (CRP) and vitamin K antagonists use (FIX). Results Mean age was 55.6years, mean eGFR 86.0 (12SD) mL1.73m- ² and median UACR 0.4mgmmol-1 (25th, 75th percentile; 0.3, 0.7). All coagulation factors showed a procoagulant shift with lower renal function and albuminuria. For example, FVIII was 22IUdL-1 (95% CI, 13-32) higher in the eGFR <1st percentile compared with the >50th percentile, and FVIII was 12IUdL-1 (95% CI, 3-22) higher in the UACR >99th percentile compared with the <50th percentile. PWV was positively associated with coagulation factors FIX and FXI in continuous analysis; per m/s difference in PWV, FIX was 2.0IUdL-1 (95% CI, 0.70-3.2) higher. Conclusions Impaired renal and vascular function was associated with higher levels of coagulation factors, underlining the role of renal function and vascular function in the development of venous thrombosis.

The Rebalanced Hemostasis System in End-stage Liver Disease and Its Impact on Liver Transplantation.

There are 3 physiological phases of action in the modern view of hemostasis. Primary hemostasis begins with endothelial injury, exposure of von Willebrand factor (vWF), platelet activation and aggregation, and an initial thrombin “burst.” Coagulation then follows with activation of the coagulation cascade, through extrinsic and intrinsic pathways in a positive feedback loop activated by thrombin and the formation of the fibrin mesh and fortification of the classic clot. Lastly, fibrinolysis must occur through the action of anticoagulant proteins and enzymes to avoid pathologic thrombus formation. Primary hemostasis is typically measured through platelet counts, vWF levels, platelet function assays, and bleeding time. Coagulation is generally measured by prothrombin time (PT) or international normalized ratio (INR) and activated partial thromboplastin time (aPTT) representing the intrinsic and extrinsic pathways of the clotting cascade, respectively. Although infrequently performed clinically, specific procoagulant factor levels can be measured. Fibrinolysis can generally be measured through fibrinogen levels, protein C and S levels, antithrombin III (ATIII) activity, euglobulin lysis time (ELT), and direct measurements of anticoagulant proteins (PAI-1, TAFI).1 There are also in vitro whole blood measures of the complete clotting system using thromboelastography (TEG), rotational thromboelastometry (ROTEM), and sonorheometry, which can give an overall assessment of the different stages of hemostasis, including the intrinsic fibrinolytic and antifibrinolytic pathways.2 In patients with cirrhosis every stage of hemostasis may be altered, putting them at risk for both bleeding and thrombosis. Classically, patients with cirrhosis have been thought of as “autoanticoagulated” because of an elevated INR and baseline thrombocytopenia owing to splenic sequestration and portal hypertension. Although routine tests such as platelet counts, INR, and aPTT may accurately reflect bleeding risk in general populations, multiple studies have shown that patients with cirrhosis have deficiencies in both the procoagulant and anticoagulant pathways, leading to a “rebalanced” coagulation system.3,4 In regard to primary hemostasis, patients with cirrhosis typically have a decreased number of circulating platelets. This is related to splenic sequestration, more rapid turnover and shorter half-life of platelets secondary to splenomegaly, and decreased production related to lower amounts of hepatic thrombopoetin.5,6 There may also be an immunologic component, although this appears to be a minor contributor.7 The decreased platelet count may be expected to increase the risk for bleeding, but patients with cirrhosis also have elevated levels of vWF, which increases in proportion to the severity of liver disease.8 In addition, there is a decrease in ADAMTS13, the vWF cleaving protein, and despite the underlying thrombocytopenia this increase in vWF may actually increase platelet adhesion.9,10 A study by Tripodi et al11 showed that in patients with cirrhosis a minimum platelet count of around 55×109/L is adequate for thrombin generation, allowing normal clot formation, and levels above 100×109/L have no increased benefit in primary hemostasis or in fibrin mesh formation when compared with controls. In some patients, these compensatory mechanisms may actually result in enhanced platelet adherence rather than dysfunctional primary hemostasis. In the second stage of hemostasis, clotting factors activate and begin to produce thrombin, predominantly on the surface of activated platelets, leading to subsequent deposition of the cross-linked fibrin mesh. In patients with cirrhosis, decreased levels of procoagulant proteins, such as factors II, V, VII, IX, X, and XI, suggest the potential for an anticoagulated state. In fact, 1 study showed a decrease in the activity of procoagulant proteins to as low as 20% to 46% in correlation with the severity of cirrhosis and portal hypertension.12 These deficiencies are easily seen in the standard clinical laboratory measurements of the INR and PT.