Plasma Concentrations Of Prothrombin Fragment Research Articles

Postprandial factor VII activation does not increase plasma concentrations of prothrombin fragment 1 + 2 in patients with morbid obesity

IntroductionIncreased postprandial factor VII activation is observed after high-fat meals, but is not accompanied by thrombin formation in normal weight individuals. Obesity is associated with a higher circulating concentration of tissue factor (TF) and postprandial uptake of lipopolysaccharide (LPS), and this may increase thrombin formation after high-fat meals. We therefore compared postprandial effects of high-fat meals and low-fat meals on biomarkers of coagulation activation in patients with morbid obesity and investigated whether the response was associated with the gut bacteria composition. Materials and methodsA controlled cross-over study was conducted in obese patients (15 women, 5 men, mean BMI = 44.1 kg/m2), where high-fat meals (67 E% fat) and low-fat meals (16 E% fat) were served at 8:15 and 10:00 in a random order on two study days within one week. Blood samples were collected at 08:00 (fasting), 12:00, and 14:00 and analysed for triglycerides, activated FVII (FVIIa), TF, FVIIa-antithrombin (FVIIa-AT), prothrombin fragment 1 + 2 (F1+2), and TF pathway inhibitor (TFPI). The gut bacteria composition, measured as gram-negative bacteria and diversity, was analysed in faecal samples. ResultsTriglycerides, FVIIa, and FVIIa-AT increased significantly after high-fat meals, whereas F1 + 2 decreased equally and significantly over time after both meals. There were no significant changes in TF and TFPI over time. The postprandial changes in F1 + 2 and TFPI after high-fat meals were negatively correlated with diversity. ConclusionsIncreased postprandial FVIIa is not accompanied by thrombin formation four hours after high-fat meals in patients with morbid obesity, possibly due to FVIIa-inhibition by AT.

Effect of infective endocarditis on blood coagulation and platelet activation and comparison of patients with to those without embolic events

Inflammation-induced procoagulant changes and alterations in platelet activity appear to play an important role in thromboembolic complications of infective endocarditis (IE). The aim of this study was to investigate systemic coagulation activity, fibrinolytic capacity, and platelet activation in IE patients with and without embolic events by measuring the plasma levels of prothrombin fragment 1 + 2, thrombin–antithrombin III complex, plasminogen activator inhibitor-1, β-thromboglobulin, and platelet factor 4. The study included 76 consecutive patients with definite IE according to the Duke criteria. Among them, 13 (17.1%) had major embolic events. Plasma concentrations of prothrombin fragment 1 + 2 (3.2 ± 1.3 vs 1.7 ± 0.7 and 1.4 ± 0.7 nmol/L, p <0.001, respectively) and thrombin–antithrombin (7.3 ± 1.5 vs 2.9 ± 1.2 and 2.2 ± 1.1 ng/ml, p <0.001, respectively) were elevated in patients with embolic events compared with both patients without embolic events and control subjects. Similarly, patients with embolic events had increased plasma levels of β-thromboglobulin (63.3 ± 10.9 vs 33.1 ± 11.6 and 19.1 ± 10.6 ng/ml, p <0.001, respectively) and platelet factor 4 (106.0 ± 28.7 vs 50.3 ± 16.7 and 43.0 ± 15.8 ng/ml, p <0.001, respectively) compared with those without embolic events and the control group. Embolic patients also had higher plasminogen activator inhibitor-1 levels than both nonembolic patients and healthy subjects (14.4 ± 6.4 vs 8.6 ± 5.9 and 5.4 ± 4.3 ng/ml, p = 0.002, respectively). In conclusion, IE patients with subsequent thromboembolism have increased systemic coagulation activation, enhanced platelet activity/damage, and impaired fibrinolysis. The resulting imbalance produces a sustained hypercoagulable state that may contribute to the increased risk of thromboembolic events in this particular group.

Prothrombotic coagulation abnormalities preceding the hemolytic-uremic syndrome.

The hemolytic-uremic syndrome is a thrombotic complication of Escherichia coli O157:H7 infection. It is not known whether the coagulation abnormalities precede, and potentially cause, this disorder. In 53 children infected with E. coli O157:H7, we measured a panel of markers indicating activation of the clotting cascade and renal function within four days after the onset of illness. These markers were measured again in as many as possible of the 16 children in whom the hemolytic-uremic syndrome developed. The children in whom the hemolytic-uremic syndrome subsequently developed had significantly higher median plasma concentrations of prothrombin fragment 1+2, tissue plasminogen activator (t-PA) antigen, t-PA-plasminogen-activator inhibitor type 1 (PAI-1) complex, and D-dimer than children with uncomplicated infection. These abnormalities preceded the development of azotemia and thrombocytopenia. When the hemolytic-uremic syndrome developed, the urinary concentrations of beta2-microglobulin and N-acetyl-beta-glucosaminidase rose significantly (P=0.03 for both increases); the plasma concentrations of t-PA antigen, t-PA-PAI-1 complex, D-dimer, and plasmin-antiplasmin complex also increased significantly. The concentration of t-PA antigen correlated with that of the t-PA-PAI-1 complex in a linear regression model (squared correlation coefficient, 0.80; P<0.001). In the hemolytic-uremic syndrome, thrombin generation (probably due to accelerated thrombogenesis) and inhibition of fibrinolysis precede renal injury and may be the cause of such injury.

Cardiopulmonary Bypass With Heparin-Coated Circuits and Reduced Systemic Anticoagulation

Background. The improved biocompatibility of the cardiopulmonary bypass circuits made possible by the use of surface-immobilized heparin may allow for a reduction in the amount of heparin administered systemically. This study was performed to elucidate the effects of cardiopulmonary bypass using heparin-coated circuits and reduced heparinization on hemostatic variables and clinical outcome.Methods. Thirty patients scheduled to undergo myocardial revascularization were randomized to have either a heparin-coated or an uncoated cardiopulmonary bypass circuit. Anticoagulation was induced with heparin (100 IU/kg in the coated group and 300 IU/kg in the uncoated group) and the activated clotting time was kept over 200 and 480 seconds in the coated and uncoated groups, respectively.Results. The postoperative overnight loss of hemoglobin through the drains was lower in the heparin-coated group (43.6 g; range, 18.5–69.0 g) than in the uncoated group (73.0 g; range, 32.2–137.7 g) (p = 0.0015). Plasma concentrations of prothrombin fragment 1 + 2 and D-dimer were significantly more elevated after cardiopulmonary bypass in the coated group than they were in the uncoated group. Two patients in the coated group had a stroke postoperatively.Conclusions. The reduction in systemic heparinization was associated with thrombin formation, which may predispose to intravascular and cardiopulmonary bypass circuit clotting. Therefore, generous systemic heparinization may still be prudent despite the improved biocompatibility offered by heparin-coated surface.(Ann Thorac Surg 1997;63:438–44)

Increased Activation of the Haemostatic System in Men at High Risk of Fatal Coronary Heart Disease

The haemostatic system was examined in 2951 men aged 50 to 61 years, clinically free of cardiovascular disease, who were ranked according to a risk score for fatal coronary heart disease (CHD). Risk was judged from their serum cholesterol concentration, systolic blood pressure, body mass index and smoking habit. The status of the factor VII-tissue factor pathway was estimated from the plasma levels of factor VII coagulant activity, factor VII antigen and activated factor VII. Activation of factor IX was assessed from the plasma concentration of factor IX activation peptide. Activity within the common pathway was measured as the plasma concentrations of prothrombin fragment 1 + 2 and fibrinopeptide A. All 6 markers of haemostatic status were positively and statistically significantly associated with risk, providing further evidence for a hypercoagulable state in men at high risk for fatal CHD. Plasma fibrinogen and serum triglyceride concentrations were also graded positively with risk.

Activation of the Hemostatic Mechanism During Thrombolysis in Patients With Unstable Angina Pectoris

In patients with myocardial infarction, thrombolytic therapy induces a paradoxical activation of the hemostatic mechanism. In patients with unstable angina, the effect of thrombolysis on the coagulation cascade is unknown. We prospectively measured the plasma concentrations of prothrombin fragment 1 + 2 and fibrinopeptide A in consecutive patients with unstable angina randomized to receive placebo alone (n = 23), streptokinase 1,500,000 IU over 1 hour followed by a 48-hour placebo infusion (n = 21), or streptokinase 250,000 over 1 hour followed by a continuous infusion of 100,000 IU per hour over 48 hours (n = 20). All the patients received intravenous heparin for 72 hours. The plasma levels of the different markers were measured at baseline, 90 minutes, 24 hours, and 48 hours after the start of therapy. The median baseline plasma concentrations of prothrombin fragment 1 + 2 and fibrinopeptide A were similar in the three treatment groups. In comparison with placebo, an increase in plasma prothrombin fragment 1 + 2 and fibrinopeptide A, was observed after 90 minutes in the two groups receiving thrombolysis. After 24 and 48 hours, the prothrombin fragment 1 + 2 levels remained significantly higher only in the patients receiving the 48-hour streptokinase infusion. In patients with unstable angina, thrombolytic therapy induces an activation of the hemostatic mechanism, despite concomitant heparin administration; in those receiving a prolonged streptokinase infusion, the activation of coagulation persists for as long as the drug is administered.

Aspects of haemostatic function in healthy subjects with microalbuminuria — A potential atherosclerotic risk factor

Microalbuminuria, i.e., slightly elevated urinary albumin excretion rate (UAER), notifies increased risk for atherosclerotic disease and may reflect an early generalized vascular abnormality in healthy subjects. This study was designed in order to examine whether such abnormality is associated with a shift of the haemostatic balance in prothrombotic direction. The following haemostatic factors were measured in two representative groups of clinically healthy subjects, 28 with microalbuminuria (UAER of 6.6–150 μg/min) and 60 age- and sex-matched controls with normoalbuminuria (UAER < 6.6 μg/min): Coagulation factors: blood platelet count and mean volume, plasma Factor VII antigen concentration and coagulant activity, and plasma concentrations of prothrombin fragment 1+2, thrombin-antithrombin III complexes, fibrinogen, and fibrinopeptide A; fibrinolytic and endothelial factors: plasma concentrations of tissue plasminogen activator antigen and plasminogen activator inhibitor type 1 antigen; and endothelial factor: plasma von Willebrand factor antigen concentration. The fibrinolytic and endothelial factors were measured both before and after 10 minutes of venous occlusion of the arm. None of the haemostatic factors were significantly altered in the microalbuminuric group. Plasma fibrinogen concentration tended to be elevated but not statistically significant ((mean (95% C.I.) 7.8 (7.2–8.3) vs. 7.2 (6.9–7.5) μmol/l; p<0.1). Neither did any of the haemostatic factors correlate with UAER in regression analyses. It is concluded that the haemostatic balance is unaltered in healthy subjects with microalbuminuria. It is unlikely that a prothrombotic state is present as an intermedial factor early in a causal chain between microalbuminuria and atherosclerotic vascular disease.

Persistent activation of coagulation mechanism in unstable angina and myocardial infarction.

The blood coagulation system is activated in the acute phase of unstable angina and acute myocardial infarction. However, it remains unclear whether augmented function of the hemostatic mechanism serves only as a marker of the acute thrombotic episode or whether a hypercoagulable state persists for a prolonged period after clinical stabilization. We prospectively measured the plasma concentrations of prothrombin fragment 1 + 2 (F1 + 2) and fibrinopeptide A (FPA) in consecutive patients presenting with unstable angina (n = 81) or acute myocardial infarction (n = 32), respectively. At 6 months, plasma determinations were repeated in patients experiencing an uneventful clinical course (unstable angina, n = 57; myocardial infarction, n = 23). We quantitated the plasma levels of F1 + 2 and FPA in control patients with stable angina (n = 37) or healthy individuals (n = 32) who were matched for age and sex. The median plasma concentrations of F1 + 2 and FPA are significantly higher in patients presenting with unstable angina (F1 + 2, 1.08 nmol/L; FPA, 2.4 nmol/L) or acute myocardial infarction (F1 + 2, 1.27 nmol/L; FPA, 3.55 nmol/L) compared with patients with stable angina (F1 + 2, 0.74 nmol/L; FPA, 1.3 nmol/L; P < .0001) or healthy individuals (F1 + 2, 0.71 nmol/L; FPA, 0.80 nmol/L; P < .0001). At 6 months, the median plasma levels of F1 + 2 in patients exhibiting an uneventful clinical course did not differ from values obtained at admission (unstable angina, 1.26 versus 1.07 nmol/L, P = NS; myocardial infarction, 1.22 versus 1.29 nmol/L, P = NS), whereas the median plasma levels of FPA in the same two subpopulations were significantly reduced (unstable angina, 1.1 versus 2.9 nmol/L, P = .0003; myocardial infarction, 1.1 versus 3.0 nmol/L; P = .0028). During the acute phase of unstable angina and myocardial infarction, patients exhibit increased coagulation system activity. Over the next 6 months, patients with unstable angina or myocardial infarction experiencing an uneventful clinical course manifest a persistent hypercoagulable state with minimal generation of fibrin.

Characterization of Prothrombin Activation during Cardiac Surgery by Hemostatic Molecular Markers

Prothrombin activation represents the key regulatory step in the hemostatic process. Once formed, thrombin contributes to the generation of fibrin as well as the activation of platelets and fibrinolysis. Failure to suppress thrombin formation during cardiac surgery could result in disorders of hemostasis and thrombosis in the perioperative period. The aim of this study was to determine the time course for prothrombin activation during the perioperative period associated with cardiac surgery. We measured prothrombin activation during the perioperative period in 19 adult patients undergoing primary cardiac surgery using enzyme-linked immunosorbent assays for the detection of thrombin formation (prothrombin fragment 1.2 and thrombin-antithrombin III complex) and thrombin activity (fibrinopeptide A and fibrin monomer). Blood samples were obtained preoperatively; at 30-min intervals during cardiopulmonary bypass (CPB); and 1, 3, and 20 h after completion of CPB. Despite anticoagulation with heparin, plasma concentrations of prothrombin fragment 1.2, thrombin-antithrombin III complex, and fibrin monomer increased throughout CPB. Peak concentrations for all hemostatic markers occurred in the samples obtained 3 h after completion of CPB. By the morning after surgery, plasma prothrombin fragment 1.2 returned to preoperative concentrations; however, fibrinopeptide A and fibrin monomer concentrations remained significantly increased (P < 0.05) compared to preoperative values. These data clearly demonstrate the occurrence of prothrombin activation and thrombin activity during CPB despite heparin concentrations adequate to maintain the activated clotting time greater than 400 s. Hemostatic markers for the activation of prothrombin demonstrated peak concentrations 3 h after completion of CPB with a return to baseline concentrations by the morning after surgery. Markers for thrombin activity, however, suggest the presence of active thrombin through the morning after surgery. Further investigations will be necessary to determine the role of hemostatic activation in thrombotic complications after cardiac surgery.

Activation of prothrombin accompanying thrombolysis with recombinant tissue-type plasminogen activator

Increases in thrombin activity in patients given fibrinolytic agents for acute myocardial infarction have been shown to be important in limiting the ultimate success of coronary thrombolysis. The present study was designed to determine whether increases in thrombin activity reflect, in part, activation of prothrombin accompanying thrombolysis. Plasma concentrations of prothrombin fragment 1.2, a polypeptide released when prothrombin is activated by factor Xa, were measured in 22 patients with acute myocardial infarction before and after treatment with 100 mg of recombinant tissue-type plasminogen activator (rt-PA). Concentrations of prothrombin fragment 1.2 increased from 0.83 ± 1.1 nM(mean ± SD) before rt-PA infusion to 1.5 ± 1.5 nM2 h after initiation of the infusion (p < 0.05). After a 5,000-U intravenous dose of heparin given at the end of the infusion of rt-PA, concentrations of prothrombin fragment 1.2 decreased from 1.8 ± 1.5 to 1.1 ± 0.9 nM(n = 20, p < 0.05), although values were still increased compared with concentrations before rt-PA.These results indicate that thrombin activity increases in patients given rt-PA at least in part because of activation of the coagulation system leading to activation of prothrombin. Thus, inhibition of the reactions involving coagulant proteins that lead to activation of prothrombin may be of value as conjunctive treatment to potentiate the efficacy of pharmacologic thrombolysis.

Induction of thromboses within renal grafts by high-dose prophylactic OKT3

Among 93 consecutive kidney-transplant patients who received prophylactic OKT3 10 mg/day for 2 weeks, 9 had intragraft thromboses within 2 weeks of transplantation. The thromboses were in graft artery in 1 patient and veins in 3. The other 5 had thromboses in glomerular capillaries and thrombotic microangiopathy similar to that of haemolytic-uraemic syndrome. All attempted treatments failed, and the 9 grafts had to be removed. The finding that plasma concentrations of prothrombin fragment 1 and 2 were higher 4 h after the first OKT3 dose in OKT3 recipients than in transplant patients who received other prophylaxis (mean 5·88 [SEM 0·76] vs 2·25 [0·59] nmol/l, p < 0·01) confirms that OKT3 has procoagulant effects in vivo.