Activated Protein C-protein C Inhibitor Research Articles

Antiphospholipid antibodies in patients with myocardial infarction with and without obstructive coronary arteries.

Recent studies demonstrate that prothrombotic antiphospholipid antibodies (aPL) are overrepresented in patients with myocardial infarction (MI) due to coronary artery disease (MICAD). However, it is not known whether aPL differ between the two subsets of MI: MICAD and MI with nonobstructive coronary arteries (MINOCA). To determine whether aPL are associated with MINOCA or MICAD, or with hypercoagulability as assessed by activated protein C-protein C inhibitor (APC-PCI) complex. Well-characterized patients with MINOCA (n = 98), age- and gender-matched patients with MICAD (n = 99), and healthy controls (n = 100) were included in a cross-sectional case-control study. Autoantibodies (IgA/G/M) targeting cardiolipin and β2 glycoprotein-I and specific nuclear antigens were analyzed by multiplexed bead technology. The concentration of APC-PCI was determined as a measure of hypercoagulability by an immunofluorometric sandwich assay. Both prevalence and titers of aPL of the IgG isotype (anti-cardiolipin and/or anti-β2 glycoprotein-I) were higher in patients with MINOCA and MICAD than in controls. aPL IgG positivity was twice as frequent among patients with MICAD than MINOCA (11% vs. 6%, nonsignificant). We observed no group differences regarding aPL IgA/M or antibodies targeting specific nuclear antigens. Levels of APC-PCI were elevated in aPL IgG-positive compared to aPL IgG-negative MICAD patients. aPL IgG, but not IgA/M, are enriched particularly in patients with MICAD but also in patients with MINOCA, as compared to controls. Interestingly, signs of hypercoagulability-measured by increased levels of the APC-PCI complex-were present in aPL IgG-positive MICAD patients, indicating an association with functional disturbances of the coagulation system.

Coagulation, Fibrinolysis and Inhibitors in Failing Filters during Continuous Venovenous Hemofiltration in Critically Ill Patients with Acute Kidney Injury: Effect of Anticoagulation Modalities

Introduction: The mechanisms of early filter failure and clotting with different anticoagulation modalities during continuous venovenous hemofiltration (CVVH) are largely unknown. Methods: Citrate, heparin and no anticoagulation were compared. Blood was drawn pre- and post filter up to 720 min. Concentrations of the thrombin-antithrombin (TAT), activated protein C-protein C inhibitor (APC-PCI), and type I plasminogen activator inhibitor (PAI-1) were determined. Results: In case of early filter failure (<24 h), inlet concentrations of TAT and APC-PCI were higher over time, irrespective of anticoagulation. There was more production of APC-PCI and platelet-derived PAI-1 in the filter after 10 min in the heparin group than in other groups. In clotting filters, production of APC-PCI and PAI was also higher with heparin than citrate. Conclusion: Coagulation activation in plasma and inhibition of anticoagulation in plasma and filter may partly determine early CVVH filter failure due to clotting, particularly when heparin is used. Regional anticoagulation by citrate circumvents the inhibition of anticoagulation and fibrinolysis by platelet activation following heparin.

APC-PCI complex levels for screening of AAA in patients with peripheral atherosclerosis

To evaluate the use of activated protein C-protein C inhibitor (APC-PCI) complex levels for detection of abdominal aortic aneurysm (AAA) in patients with peripheral atherosclerotic disease (PAD). APC-PCI levels and aortic diameter evaluated in 511 PAD patients without previously known AAA followed-up concerning survival for 4.8(0.5) years. AAA was found in 13% of patients. Aortic diameter correlated (r = 0.138; p = 0.002) with APC-PCI levels which were higher (0.40[0.45] vs. 0.30[0.49] μg/l; p = 0.004) in patients with AAA. This difference persisted in multivariate analysis (p = 0.029). A threshold value of APC-PCI ≥0.15 μg/L showed a specificity of 11%, a sensitivity of 97% and a negative predictive value of 96% for an AAA diagnosis. APC-PCI levels were higher in patients with AAA, and showed high sensitivity but low specificity for the diagnosis and can therefore not be considered as a screening tool in PAD patients. An AAA prevalence of 13% in patients with PAD indicates a need for AAA screening within this population.

Coagulation, fibrinolysis, and platelet activation in patients undergoing open and endovascular repair of abdominal aortic aneurysm

Endovascular aneurysm repair (EVAR) is associated with an improved perioperative mortality compared to open surgical repair. This benefit may reflect reduced incidence of microvascular and macrovascular thrombotic complications after EVAR. The purpose of this study was to review and compare the effects of abdominal aortic aneurysm (AAA), open surgical repair, and EVAR on coagulation, fibrinolysis, and platelet activation. A MEDLINE (1966-2010) and Cochrane library search for articles relating to the effects of AAA, open surgical repair, and EVAR on hemostasis was performed utilizing and cross-linking terms such as clotting, fibrinolysis, AAA, EVAR, and open surgical repair. Studies with a small cohort of patients (less than 7) or in which values of assessed biomarkers were not included were rejected. AAA is associated with increased thrombin generation, activity, and fibrin turnover as evidenced by increased plasma levels of thrombin-antithrombin III-complex (TAT), activated protein C-protein C inhibitor (APC-PCI), fibrin-monomer-fibrinogen (FM-F), F1+2, fibrinogen, and D-dimer. The extent of hemostatic derangement correlates with the volume of intraluminal thrombus. This procoagulant state is exaggerated in the immediate perioperative period after both open surgical repair and EVAR, but is attenuated at medium-term follow-up although not normalized. The resultant prothrombotic diathesis after open surgical repair and EVAR may account for the high level of perioperative thrombotic complications.

Markers of Proteolysis, Fibrinolysis, and Coagulation in Relation to Size and Growth Rate of Abdominal Aortic Aneurysms

We evaluated whether matrix metalloproteinases (MMPs) 2 and 9, their inhibitors, markers for fibrinolysis, and thrombin activation are associated with diameter and growth of abdominal aortic aneurysms (AAAs). Matrix metalloproteinases 2 and 9, tissue inhibitor of MMPs (TIMP-1), serpine-1, tPa-serpine-1, and activated protein C- protein C inhibitor (APC-PCI) complex were analyzed in 353 patients with AAA grouped according to AAA size, and 219 gender- and age-matched healthy individuals. Follow-up of AAA growth for up to 7 years was possible in 178 of 353 patients. At baseline, all groups of patients with AAA showed lower levels of MMP-2 and -9, and higher levels of TIMP-1, serpine-1, and t-Pa-serpine-1 than controls. Matrix metalloproteinase 2 correlated inversely and APC-PCI complex correlated directly with AAA diameter. We found no correlations between markers for proteolysis, fibrinolysis, coagulation, and yearly AAA growth. Matrix metalloproteinase 2 is lower and APC-PCI higher in patients with larger AAA, but the relevance of the markers for AAA growth is far from clarified.

Coagulation activation and ultrasound characteristics in patients with carotid artery disease

Introduction Elevated levels of markers for thrombin activation are associated with plaque echogenicity and degree of stenosis in patients with carotid artery stenosis. The Activated Protein C-Protein C Inhibitor (APC-PCI) complex reflects activation of the Protein C system and is a measure of thrombin generation. The aim of the present study was to examine APC-PCI complex in patients undergoing thrombendartherectomy for carotid artery stenosis, and to relate the findings to clinical characteristics and plaque morphology as determined by ultrasound. Materials and Methods Blood was obtained from 125 patients (39 female, median age 71 years) with carotid artery stenosis admitted from September 2005 to May 2007. The APC-PCI complex was measured using a sandwich immunofluorometric method and compared to an age- and sex-matched healthy control-group. Clinical and demographic characteristics, routine laboratory markers and ultrasound characteristics were analysed using univariate and multivariate analysis. Results APC-PCI complex concentration was significantly increased in patients with carotid artery stenosis (median 0.21 µg/L; 10th to 90th percentile 0.15–0.36) compared to a healthy control-group (0.19 µg/L; 0.11–0.31; P = .009). There was no significant difference in APC-PCI-values between asymptomatic (n = 48) and symptomatic (n = 77) patients with carotid artery stenosis (0.22 vs. 0.20 µg/L; p = 0.626). Patients with minor stroke (n = 31) had a higher median APC-PCI-concentration (0.27 µg/L; 0.15–0.63) than patients with amaurosis fugax (0.19 µg/L; 0.15–0.36) or transient ischemic attack (0.21 µg/L; 0.12–0.36) (p = 0.016). No association was found between APC-PCI-values and the degrees of carotid artery stenosis or the time from the latest neurological symptoms to blood sampling. Patients with echolucent plaques had significantly lower APC-PCI concentrations (0.20 µg/L; 0.14–0.35 vs. 0.24 µg/L; 0.15–0.60; p = 0.043), according to the Gray-Weale classification. Conclusions Patients with carotid artery disease exhibit increased concentrations of APC-PCI compared to a healthy control-group, particularly those patients with echogenic plaques, who have significantly higher APC-PCI levels than patients with echolucent plaques.

Is Increased Thrombin Activation in Patients With Abdominal Aortic Aneurysms Dependent on Area or Volume of Aneurysm Thrombus Mass?

Does thrombin activation seen in patients with abdominal aortic aneurysms (AAA) relate to the thrombus surface area or volume within the aneurysm? A total of 130 patients with AAA were analyzed regarding levels of the complex between activated protein C-protein C inhibitor (APC-PCI) and AAA morphology. Analysis of APC-PCI complex was made using a sandwich immunofluorometric method. Increased APC-PCI concentrations were seen in patients with AAA (0.44 microg/L; P < .001 compared with controls). The correlations of APC-PCI values were r = .13, P = .13 for aneurysm size, r = .08, P = .35 for thrombus surface area, and r = .13, P = .14 for thrombus volume. APC-PCI values elevated to 0.45 microg/L in 10 patients with AAA having no or very little thrombus mass. Disappointingly, no correlation was found between thrombus surface area or volume and levels of the APC-PCI complex. Mechanisms other than the AAA-sac thrombus must be evaluated as cause of thrombin activation in patients with AAA.

Associations Between Statin Treatment and Markers of Inflammation, Vasoconstriction, and Coagulation in Patients With Abdominal Aortic Aneurysm

The association of statins with markers of inflammation, vasoconstriction, and coagulation was evaluated in 325 patients with abdominal aortic aneurysm with respect to statin treatment or not. Variables evaluated included routine laboratory markers, lipids, homocysteine, endothelin-1, matrix metalloproteinases (MMP)-2 and -9, and activated protein C-protein C inhibitor (APC-PCI) complex. Statin-treated patients were more often male (85% vs 75%; P = .024) and had ischemic heart disease (57% vs 19%; P < .0001). They showed lower levels of cholesterol (P < .0001), homocysteine (P = .027), MMP-9 (P = .038), and endothelin-1 (P = .005), and higher levels of APC-PCI complex (P = .042). Differences persisted in logistic regression for cholesterol (P < .0001), APC-PCI complex (P = .034), and homocysteine (P = .021). Statin-treated patients with abdominal aortic aneurysm show higher APC-PCI complex and lower homocysteine levels. Whether this translates into lower risk for aneurysm expansion or rupture will be evident from further follow-up.

Venous thromboembolism in carriers of the Factor V Leiden mutation and in patients without known thrombophilic risk factor; prediction of recurrence and APC–PCI complex concentration and/or soluble thrombomodulin antigen and activity

Background The complex between activated protein C (APC) and the protein C inhibitor (PCI) is a sensitive indicator of the degree of activation of blood coagulation and higher concentrations have been measured in carriers of the FV Leiden mutation who were in the recovery phase after treatment for venous thromboembolism (VTE). Objectives The main purpose of this study was to correlate the APC–PCI complex concentration to thrombomodulin activity and antigen concentration in the same group of patients. We also add a prospective clinical follow-up of the VTE recurrence after 1 year to investigate if the markers can predict the risk for a new VTE. Patients/Methods Blood samples were collected from 50 patients with the FV Leiden mutation and 132 without any known risk factor for thrombophilia after finished treatment. Results The APC–PCI complex, s-TM activity and the quotient (s-TM activity) / (s-TM antigen) were higher in VTE patients with FV Leiden. In total, there were 19 VTE recurrences (10%) after 1 year. The OR for recurrence was 1.9 (95% CI 0.68–5.0) in all VTE patients with elevated APC–PCI complex (above 75th percentile) and 3.6 (95% CI 1.1–12) in VTE patients without any known risk factor for thrombophilia and with elevated s-TM activity. Conclusion The APC–PCI complex concentration, s-TM activity and the quotient (s-TM activity) / (s-TM antigen) were higher in VTE patients with FV Leiden. The s-TM activity showed higher OR for recurrence of VTE in patients without known thrombophilic risk factor. Both methods could be sensitive markers of increased risk for venous thrombosis.

The APC–PCI complex concentration predicts outcome of aortic surgery

IntroductionCoagulation activation may be related to complications during surgery for abdominal aortic aneurysm. The complex formed between activated protein C (APC) and the serpin, protein C inhibitor (PCI), is a sensitive indicator of the activation of blood coagulation. The purpose of the study was to establish whether the APC–PCI complex can provide information useful for the assessment of outcome after aortic surgery. Materials and methodsIn 38 patients, the APC–PCI complex was initially determined every 6 h and daily from day three. Protein C, antithrombin, global haemostatic tests, and clinical scores were investigated. Length of stay at the intensive care unit (ICU) and hospital, and vital status up to two years were recorded. ResultsThe median APC–PCI complex concentration in samples drawn 0–6 h after surgery was more than 20-fold higher than the upper limit of the reference interval. The level then declined rapidly, but remained elevated during the first two days. In patients with higher initial APC–PCI complex concentrations, Sequential Organ Failure Assessment (SOFA) scores were higher, the ICU stay was longer, and survival up to two years was lower. Patients who did not survive the ICU care had higher APC–PCI complex levels at 6–12 h and 12–18 h. ConclusionsHigh concentrations of the APC–PCI complex within 6–18 h after the aortic surgery predict a sinister outcome. The results suggest that the APC–PCI complex is indicative of the severity of the disease.

Decreased protein C activation in patients with fulminant hepatic failure

Objective. Abnormalities of the blood coagulation system have an influence on outcome in patients with fulminant hepatic failure (FHF). The protein C (PC) pathway is one of the main modulators of the blood coagulation system. The role of the PC pathway in FHF is not clear. In the present study, we evaluated endothelial cell injury and the grade of activated protein C (APC) generation in FHF patients. Material and methods. The effect of APC on the expression of tumor necrosis factor (TNF)-α and monocyte chemoattractant protein (MCP)-1 from LI90 stellate cells was also evaluated. This study comprised 5 patients with FHF, 6 with acute hepatitis (AH), 12 with chronic hepatitis (CH) and 20 healthy subjects. Results. The plasma concentrations of thrombin-antithrombin complex and thrombomodulin were significantly increased in FHF patients compared with those in AH patients and healthy subjects. The circulating levels of activated protein C-protein C inhibitor (APC-PCI) complex and the APC-PCI/PC ratio were significantly decreased in patients with FHF compared to healthy controls. APC significantly inhibited in vitro the expression of TNFα and MCP-1 from LI90 stellate cells. Conclusions. This study demonstrated enhanced endothelial cell injury in association with decreased PC activation and hypercoagulability in FHF.