Data from in vitro and animal experiments suggest that progressive endothelial damage with subsequent activation of coagulation and inflammation have a key role in hypertensive crisis. However, clinical investigations are scarce. We hypothesized that hypertensive emergencies are associated with enhanced inflammation, endothelial- and coagulation activation. Thus, we enrolled 60 patients admitted to an emergency department in a prospective, cross-sectional study. We compared markers of coagulation, fibrinolysis (<em>prothrombin</em> <em>fragment</em> F(<em>1</em>+<em>2</em>), plasmin-antiplasmin complexes, plasmin-activator inhibitor, tissue plasminogen activator), platelet- and endothelial activation and inflammation (P-selectin, C-reactive protein, leukocyte counts, fibrinogen, soluble vascular adhesion molecule-<em>1</em>, intercellular adhesion molecule-<em>1</em>, myeloperoxidase and asymmetric dimethylarginine) between hypertensive emergencies, urgencies and normotensive patients. In hypertensive emergencies, markers of inflammation and endothelial activation were significantly higher as compared with urgencies and controls (P<0.05). Likewise, plasmin-antiplasmin complexes were 75% higher in emergencies as compared with urgencies (P<0.00<em>1</em>), as were tissue plasminogen-activator levels (∼30%; P<0.05) and sP-selectin (∼40%; P<0.05). In contrast, similar levels of all parameters were found between urgencies and controls. We consistently observed elevated markers of thrombogenesis, fibrinolysis and inflammation in hypertensive emergencies as compared with urgencies. Further studies will be needed to clarify if these alterations are cause or consequence of target organ damage.

Patients with chronic obstructive pulmonary disease (COPD) are prone to clinical exacerbations that are associated with increased airway inflammation, a potent pro-thrombotic stimulus. Limited information is available on the mechanisms underlying the putative alterations of the endothelial-coagulative system during acute exacerbations. The aim was to investigate whether the activation of the endothelial-coagulative system occurs in association with the acute inflammatory response of COPD exacerbation. We monitored the blood levels of surrogate markers of inflammation: interleukin-6 (IL-6); endothelium damage: von Willebrand's factor (vWF); clotting activation: D-dimer (D-D), and <em>prothrombin</em> <em>fragment</em> <em>1</em>+<em>2</em> (F<em>1</em>+<em>2</em>); fibrinolytic response: plasminogen activator inhibitor <em>1</em> (PAI-<em>1</em>), in COPD subjects, during hospital admission and after clinical resolution. In 30 COPD subjects, IL-6, vWF, D-D and F<em>1</em>+<em>2</em> levels were elevated during exacerbation and decreased significantly at clinical stability (IL-6, p = 0.005; vWF, p < 0.00<em>1</em>; D-D, p < 0.00<em>1</em>; F<em>1</em>+<em>2</em>, p < 0.00<em>1</em>). PAI-<em>1</em> levels did not change at exacerbation compared to clinically stable situations. Positive correlations were observed between several of the markers measured. Elevation of IL-6, vWF, D-D and F<em>1</em>+<em>2</em> levels during COPD exacerbations implies a strict association between acute inflammation, endothelial activation and clotting initiation. This was not associated with a change in PAI-<em>1</em>, implying an increase in the fibrinolytic response to inflammation. The pro-thrombotic nature of COPD exacerbations sustained by enhanced clotting activation appears to be mitigated by excessive fibrinolysis.

BACKGROUND

A single bolus of dalteparin at the start of haemodialysis (HD) may prevent clot formation, but subclinical activation of platelets and coagulation may still occur. Consequently, the relationship between clinical clotting events and activation markers of platelets and coagulation before and during HD is of interest.

METHODS

The effect of tapered doses of dalteparin during 84 HD sessions (4-4.5 h) was prospectively examined in <em>1</em><em>2</em> patients. Six of the patients were treated with warfarin. The initial dalteparin dose was reduced to 50% if no clotting was observed. Clinical clotting was evaluated by inspection of the air trap every hour and by inspection of the dialyser after each session. Anti-FXa activity was measured for assessment of dalteparin activity. Markers of activated plasma coagulation, (thrombin-antithrombin (TAT) and <em>prothrombin</em> <em>fragment</em> <em>1</em>+<em>2</em> (PF<em>1</em>+<em>2</em>)) and a marker of platelet activation (beta-thromboglobulin, beta-TG), were measured before the start of and after 3 and 4 h of dialysis. Ten pre-dialytic patients with chronic renal failure served as a control group. A total of <em>2</em>30 measurements of each parameter were performed.

RESULTS

An anti-FXa activity above 0.4 IU/ml at the end of HD inhibits overt clot formation for 4 h. This was obtained by an intravenous dalteparin dose of about 5000 IU. TAT and PF<em>1</em>+<em>2</em> correlated to clinical clotting episodes (r=0.50 and 0.47, P<0.00<em>1</em>). beta-TG was not significantly correlated to clinical clotting. All parameters increased during the sessions (TAT, PF<em>1</em>+<em>2</em>, beta-TG, P<0.00<em>1</em>). When measurements during clinical clotting episodes were disregarded, all parameters were still markedly increased. Warfarin-treated patients had lower TAT and PF<em>1</em>+<em>2</em>. Dialysis patients had higher beta-TG values than pre-dialytic patients.

CONCLUSIONS

Despite clinically effective anticoagulation, obtained by dalteparin administration, platelets and coagulation are activated by HD, resulting in a potentially thrombophilic state. Warfarin treatment reduces clinical clot formation and subclinical activation of coagulation.

Clinical and epidemiologic studies demonstrate that vascular risk factors may be involved in Alzheimer disease (AD). To evaluate whether vascular abnormalities are an early feature of AD, several parameters of coagulation and fibrinolysis were assessed. Thirty patients with mild AD and 30 age-matched control subjects entered the study. All subjects performed a standardized clinical and laboratory protocol. Persons with vascular risk factors and systemic diseases were excluded. AD patients present significant increased levels of thrombomodulin (p < 0.000<em>1</em>) and sE-selectin (p < 0.03). In contrast, no difference was found between the two diagnostic groups in the levels of beta-thromboglobulin, <em>prothrombin</em> <em>fragment</em> <em>1</em>+<em>2</em>, fibrinogen, and von Willebrand factor. No other association but diagnosis was found with thrombomodulin and sE-selectin. These findings suggest that endothelial dysfunction is an early event in AD patients.

Endothelial damage plays a central role in the development of an SIRS-related Multiple Organ Dysfunction Syndrome (MODS) as a consequence of the establishment of a hemostatic imbalance between coagulation and fibrinolysis systems. Until now, sepsis is the SIRS model that has been most studied. The aim of this study was to assess the endothelial damage and the hemostatic imbalance in early stages of an SIRS of different origins, and to study if there are any differences in these disturbances between infectious and noninfectious SIRS. The endothelial damage and hemostatic changes were studied in 40 patients with SIRS (with less than <em>1</em><em>2</em> h of evolution) and an acute renal failure. Infectious SIRS was diagnosed in <em>1</em>9 cases and noninfectious SIRS in the remaining <em>2</em><em>1</em> patients. Patients with SIRS presented significantly higher values (p<0.00<em>1</em>) for factors related to endothelial damage [von Willebrand factor (vWF), thrombomodulin, tissue plasminogen activator (t-PA), and plasminogen activator inhibitor type <em>1</em> (PAI-<em>1</em>) antigen], hypercoagulability [<em>prothrombin</em> <em>fragment</em> <em>1</em>+<em>2</em> (F<em>1</em>+<em>2</em>) and thrombin-antithrombin complexes (TAT)], and fibrinolysis (D-dimer and PAI activity) with respect to the control group. However, although the group with infectious SIRS presented higher values for all the factors except for the t-PA and D-dimer with respect to SIRS of other origins, none of these differences reached statistical significance (p>0.05). Our data show that patients with SIRS and associated acute renal failure, irrespective of the origin (infectious or noninfectious), show signs of intense endothelial damage and hypercoagulability throughout the process.

BACKGROUND

A state of hypercoagulation and fibrinolytic dysfunction is present in individuals with diabetes, which may contribute to disturbed skin microcirculation and impaired ulcer healing. We have previously reported an improved outcome of chronic diabetic foot ulcers during treatment with dalteparin. In the present study we investigated the effects of dalteparin on skin microcirculation and haemostatic function.

METHODS

87 patients with diabetes, peripheral arterial obliterative disease and chronic foot ulcers were investigated in a prospective, randomised, double-blind and placebo-controlled study. They were randomised to treatment with subcutaneous injections of 5000 U dalteparin (n=44) or placebo (n=43), once daily until ulcer healing or for a maximum of six months. Plasma fibrinogen, fibrin gel structure [permeability coefficient (Ks) and fiber mass/length ratio (mu)], <em>prothrombin</em> <em>fragment</em> <em>1</em>+<em>2</em> (F<em>1</em>+<em>2</em>) antigen, plasminogen activator inhibitor-<em>1</em> (PAI-<em>1</em>) activity and tissue plasminogen activator (tPA) antigen were analysed before randomization (baseline value), and at the end of the treatment period. The skin microcirculation of the foot was investigated by transcutaneous oxygen tension (TcPO(<em>2</em>)) and laser Doppler fluxmetry (LDF).

RESULTS

The changes (Delta-values) of Ks, mu, tPA and TcPO(<em>2</em>) were higher (p<0.05) during treatment with dalteparin, as compared to the changes during treatment with placebo. At baseline, plasma fibrinogen and Ks were significantly correlated to TcPO(<em>2</em>).

CONCLUSIONS

Local skin oxygenation improved and a less thrombogenic fibrin gel structure was formed in patients treated with dalteparin. Beneficial effects on haemostatic function are likely to contribute to the improved skin oxygenation observed during treatment with dalteparin.

BACKGROUND

Receptors for vitamin D have been found in various tissues, including the vascular endothelium. The role of vitamin D in the haemostatic process is uncertain, but in vitro studies may indicate a pro-fibrinolytic effect.

METHODS

Two hundred and six subjects (<em>1</em>05 males) were included in the study. The relations between indices of calcium metabolism and haemostatic factors [tissue plasminogen activator antigen (tPA Ag), plasminogen activator inhibitor <em>1</em> (PAI-<em>1</em>), <em>prothrombin</em> <em>fragment</em> <em>1</em>+<em>2</em>, activated factor VII and total factor VII coagulant activity] and high-sensitivity C-reactive protein (HS-CRP) were examined.

RESULTS

There were significant and negative correlations between serum <em>2</em>5(OH) vitamin D and PAI-<em>1</em> and tPA Ag, and between serum <em>1</em>,<em>2</em>5(OH)<em>2</em> vitamin D and tPA Ag and HS-CRP. In a multiple linear regression model with age, gender, body mass index and smoking status as covariables, only the relation between <em>2</em>5(OH) vitamin D and tPA Ag was significant. There were no significant relations between any of the haemostatic factors tested and serum parathyroid hormone.

CONCLUSIONS

It appears that the serum level of vitamin D is related to fibrinolytic activity and to the integrity of the vascular endothelium, but the clinical importance of this observation remains to be determined.

OBJECTIVE

Recanalization is common after acute deep venous thrombosis, but the factors that contribute to its variable extent are unknown. The purpose of this study was to examine the relationship between recanalization and plasma markers of coagulation and fibrinolysis.

METHODS

Subjects with an ultrasound-confirmed deep venous thrombosis had <em>prothrombin</em> <em>fragment</em> <em>1</em>+<em>2</em> (F <em>1</em>+<em>2</em>), tissue plasminogen activator (t-PA) activity, plasminogen activator inhibitor (PAI-<em>1</em>) activity, and t-PA antigen levels determined before anticoagulation therapy. Ultrasound and plasma studies were repeated at <em>1</em>4 days, <em>1</em> month, and every 3 months for <em>1</em> year.

RESULTS

Among 7<em>1</em> enrolled subjects, F <em>1</em>+<em>2</em> levels normalized within <em>1</em>4 days. The mean t-PA activity was within the normal range at all follow-up intervals. However, the mean t-PA antigen (<em>1</em>0.7 plus minus <em>1</em>0.5 to <em>1</em>3.6 plus minus <em>1</em>3.5 ng/mL; P =.04) and PAI-<em>1</em> (9.0 plus minus 8.<em>1</em> to <em>1</em>3.<em>2</em> plus minus <em>1</em>7.3 U/mL; P =.05) levels increased between the time of presentation and day <em>1</em>4. The mean reduction in thrombus score among 44 patients who completed 9 months of follow-up was 60.9% (plus minus 4<em>2</em>.<em>1</em>%). Percent recanalization was directly associated with initial t-PA activity levels (R =.4; P =.006) and inversely related to F <em>1</em>+<em>2</em> (R = minus sign. 5; P =.004), t-PA antigen (R = minus sign.5, P =.00<em>2</em>), and PAI-<em>1</em> (r = minus sign. 5, P =.00<em>1</em>) levels. However, only initial F <em>1</em>+<em>2</em> (P =.0009) and t-PA antigen (P =.004) levels were independent predictors of the degree of recanalization.

CONCLUSIONS

Although the mechanisms by which the venous lumen is restored are still being elucidated, recanalization is inversely related to levels of activated coagulation (F <em>1</em>+<em>2</em>) and fibrinolytic inhibition (t-PA antigen) at the time of presentation.

OBJECTIVE

To investigate the prevalence of clinical and subclinical atherosclerosis in systemic sclerosis (SSc) patients and its associated features.

METHODS

Fifty unselected SSc patients and 4<em>1</em> controls, matched for sex and age, were investigated for previous cardiovascular events, cardiovascular risk factors, and ultrasonographic features of subclinical atherosclerosis in the carotid arteries, that is intima-media thickness (IMT)>> 0.9 mm or plaques. SSc patients were also investigated for disease features and previous treatment. Finally, blood samples were randomly selected from <em>2</em>7 patients and <em>1</em>8 controls to evaluate concentrations of amino-terminal propeptide of type III procollagen (PIIINP), transforming growth factor (TGF)-β, hepatocyte growth factor (HGF), soluble interleukin-<em>2</em> receptor (sIL-<em>2</em>R), IL-<em>1</em>3, E-selectin, intercellular adhesion molecule (ICAM)-<em>1</em>, plasminogen activator inhibitor (PAI)-<em>1</em>, tissue plasminogen activator (t-PA), D-dimer, and <em>prothrombin</em> <em>fragments</em> (F<em>1</em>+<em>2</em>).

RESULTS

Previous cardiovascular events were recorded in three SSc patients and no controls (p>> 0.05). Mean IMT (0.6<em>1</em>3 ± 0.<em>2</em>40 vs. 0.654 ± 0.<em>1</em>73 mm) did not differ between patients and controls (p>> 0.05), but subclinical atherosclerosis was detected in <em>1</em>4/50 SSc patients and 4/4<em>1</em> controls (p = 0.036). At multiple logistic regression analysis, mean IMT was correlated with older age [p = 0.006; odds ratio (OR) <em>1</em>.<em>2</em>76, 95% confidence interval (CI) <em>1</em>.043-<em>1</em>.5<em>1</em>6] and a higher cumulative corticosteroid intake (p = 0.0<em>1</em>7; OR <em>1</em>.<em>1</em>55, 95% CI <em>1</em>.0<em>2</em>7-<em>1</em>.300). No correlation was found with any soluble marker of disease activity and of coagulation/fibrinolysis system activation.

CONCLUSIONS

Our study confirms an increased prevalence of subclinical atherosclerosis in SSc patients and demonstrates a hitherto unknown association with corticosteroid cumulative dosage.

Laparoscopic surgery appears to be less traumatic to the patient than open surgery, but its influence upon coagulation and fibrinolysis is incompletely elucidated. Our aim was to measure markers of coagulation and fibrinolysis before, during. and after laparoscopic cholecystectomy (LC). Blood samples drawn on admission, on four occasions during operation as well as <em>2</em> hours after operation and on the first postoperative day in 50 patients undergoing elective LC were analyzed for <em>prothrombin</em> <em>fragment</em> <em>1</em>+<em>2</em> (F<em>1</em>+<em>2</em>), soluble fibrin (SF), D-dimer (DD), fibrin degradation products (FbDP), tissue-type plasminogen activator (tPA) activity and antigen, and plasminogen activator inhibitor (PAI) activity and antigen. F<em>1</em>+<em>2</em>, SF, DD, and FbDP levels increased significantly after LC. Differences between pre- and postoperative PAI and tPA levels were not significant apart from a transient increase in tPA antigen levels. tPA activity was significantly increased during operation.

It has been suggested that blood coagulation be activated and fibrinolytic activity be impaired in patients with coronary artery disease (CAD). With regard to the activation of coagulation and fibrinolysis occurring during exercise in healthy individuals, we examined the hypothesis that rehabilitative exercise in patients with CAD might give rise to an exaggerated activation of coagulation. In <em>1</em><em>2</em> patients with angiographically documented CAD without myocardial infarction within the preceding 6 months (male, age 55+/-9 years [SD]) and in <em>1</em><em>2</em> healthy controls (male, 5<em>2</em>+/-7 years), molecular markers of thrombin, fibrin, and plasmin formation were determined before and after a rehabilitative group exercise session lasting <em>1</em> hour. Resting levels of <em>prothrombin</em> <em>fragment</em> <em>1</em>+<em>2</em> were lower in patients with CAD (0.67+/-0.<em>2</em> [SE] vs <em>1</em>.04+/-0.<em>2</em> nmol/L, p <0.00<em>1</em>) and remained unchanged after exercise, whereas a significant increase was noted in controls (p <0.0<em>1</em>). After exercise, plasma levels of thrombin-antithrombin III complexes and of fibrinopeptide A increased significantly in both groups, although there were more pronounced changes in controls. Exercise resulted in a marked generation of plasmin as indicated by plasmin-alpha<em>2</em>-antiplasmin complexes increasing <em>2</em>.5-fold in patients (p <0.00<em>1</em>) and threefold in controls (p <0.00<em>1</em>). Repeated experiments in control subjects after administration of aspirin (day <em>1</em>: 500 mg; days <em>2</em> to 5: <em>1</em>00 mg) documented that differences between groups could not be attributed to aspirin medication (<em>1</em>00 mg/day) in patients with CAD. We concluded that rehabilitative exercise in patients with CAD beyond the immediate postinfarction period has no detrimental effects on thrombin, fibrin, and plasmin formation.

Bullous pemphigoid (BP) is a potentially life-threatening autoimmune blistering disease that is burdened with an increased risk of cardiovascular events. In BP, there is an interplay between inflammation and coagulation both locally, which contributes to skin damage, and systemically, which leads to a prothrombotic state. Fibrinolysis is an important defence mechanism against thrombosis, but has only been studied locally in BP and no systemic data are available. The aim of this observational study was to evaluate systemic fibrinolysis and coagulation activation in patients with BP. We measured parameters of fibrinolysis and coagulation by immunoenzymatic methods in plasma from <em>2</em>0 patients with BP in an active phase and during remission after corticosteroid treatment. The controls were <em>2</em>0 age- and sex-matched healthy subjects. Plasma levels of plasminogen activator inhibitor type <em>1</em> (PAI-<em>1</em>) antigen, PAI-<em>1</em> activity and tissue plasminogen activator (t-PA) antigen were significantly higher in the BP patients with active disease than in healthy controls (P = 0·000<em>1</em> for all), as were the plasma levels of the fibrin <em>fragment</em> d-dimer and <em>prothrombin</em> <em>fragment</em> F<em>1</em>+<em>2</em> (P = 0·000<em>1</em> for both). During remission after treatment, levels of PAI-<em>1</em> antigen and PAI-<em>1</em> activity decreased significantly (P = 0·008 and P = 0·006, respectively), and there was also a significant decrease in plasma levels of d-dimer (P = 0·000<em>1</em>) and F<em>1</em>+<em>2</em> (P = 0·000<em>1</em>). Fibrinolysis is inhibited in patients with active BP, due mainly to an increase in plasma levels of PAI-<em>1</em>. Corticosteroids not only induce the regression of BP lesions, but also reduce the inhibition of fibrinolysis, which may contribute to decreasing thrombotic risk.

BACKGROUND

Abdominal aortic aneurysm is a common condition with high mortality when rupturing. However, the condition is also associated with nonaneurysmal cardiovascular mortality. A possible contributing mechanism for the thrombosis related cardiovascular mortality is an imbalance between the activation of the coagulation system and the fibrinolytic system. The aim of the present study was to investigate haemostatic markers in patients with nonruptured abdominal aortic aneurysm with special regard to the influence of aneurysm size and smoking habits.

METHODS

Seventy-eight patients with infrarenal aortic aneurysm and forty-one controls without aneurysm matched by age, gender and smoking habits were studied. Thrombin-antithrombin (TAT), <em>prothrombin</em> <em>fragment</em> <em>1</em>+<em>2</em> (F <em>1</em>+<em>2</em>)--markers of thrombin generation, and von Willebrand factor antigen (vWFag)--considered as a reliable marker of endothelial dysfunction--were measured. Plasma levels of tissue plasminogen activator antigen (tPAag), and plasminogen activator inhibitor type <em>1</em> (PAI-<em>1</em>) were measured as markers of fibrinolytic activity. D-dimer, a marker of fibrin turnover, was also measured.

RESULTS

There were significantly higher levels of TAT and D-dimer in patients with abdominal aortic aneurysm. The highest level of TAT and D-dimer were detected in patients with large compared to small AAA.

CONCLUSIONS

The present data indicate a state of activated coagulation in patients with abdominal aortic aneurysm which is dependent by aneurysm size. The activated coagulation in AAA patients could contribute to an increased cardiovascular risk in patients also with small AAA. The possible impact of secondary prevention apart from smoking cessation has to be further evaluated and is maybe as important as finding patients at risk of rupture.

A 30-year-old female with severe factor XI deficiency of 0-<em>2</em>% acquired factor XI inhibitor following many infusions for fresh frozen plasma (FFP) for surgical procedures starting at 4 years of age. Seven months before this inhibitor was diagnosed, surgery was complicated by prolonged bleeding resistant to FFP, requiring epsilon aminocaproic acid (EACA) and surgical packing. The inhibitor was measured at <em>2</em>.<em>2</em> Bethesda units, 7 months since the last FFP. The inhibitor was confirmed as specific anti-XI and anti-XIa binding by patient's IgG to immobilized factor XI and factor XIa from whole plasma and purified IgG. For repair of a painful anterior cruciate ligament (ACL) defect she was given recombinant factor VIIa (rVIIa) at 90 mug kg(-<em>1</em>), starting one-half hour preoperatively and continued every <em>2</em> h for 8 h when haemostasis was complete. Thereafter the rVIIa was given every 3 h for two doses, and then every 4 h for four doses at which time she was discharged on EACA which was continued for 6 days. There was excellent haemostasis during and following the surgery. There was no evidence of consumptive coagulopathy, with no change in the fibrinogen, platelet count, or D-D dimer; and no increase of platelet factor 4, beta-thromboglobulin, or <em>prothrombin</em> <em>fragment</em> F <em>1</em>.<em>2</em>. The thrombin-antithrombin complex increased over baseline after <em>2</em>4 h. There was no postoperative deep vein thrombosis or pulmonary embolus. In this patient with a factor XI inhibitor, the recombinant factor VIIa was effective and safe, ensuring adequate haemostasis with no thrombotic complications. This product which was designed for patients with inhibitors to factor VIII or factor IX, and factor VII deficiency, has now been given successfully to four patients with factor XI inhibitors.

The objective of this study is to determine whether patients with systemic lupus erythematosus (SLE) and anticardiolipin antibodies (ACA) have biochemical evidence of an ongoing prothrombotic state. Using a cross-sectional analysis of a cohort design in an outpatient SLE clinic setting, 43 consecutive patients with SLE participated. Patients underwent clinical and laboratory evaluations on two separate occasions at least 3 months apart. As part of the clinical evaluation, the following were ascertained: (<em>1</em>) the ongoing use of warfarin therapy; (<em>2</em>) the presence of prior venous and arterial thromboembolic disease by history, critical review of objective tests, and examination for reflux in the deep veins of the legs as an indicator of venous thrombosis; and (3) disease-related activity by performing a lupus activity criteria count (LACC). As part of the laboratory evaluation, blood was taken on both occasions and assayed for <em>prothrombin</em> <em>fragments</em> (F<em>1</em> + <em>2</em>) and fibrinopeptide A (FPA), as indices of thrombin generation and activity, respectively, and ACA. For the analyses, patients were classified as ACA+ if the assay was abnormal on both occasions and ACA- if the assay was negative on both occasions or negative on one occasion and positive on the other. ACA+ patients had: (<em>1</em>) a significantly higher mean level of F<em>1</em> + <em>2</em> (<em>1</em>.07 nmol/L) than ACA- patients (0.79 nmol/L; P = .0<em>2</em>) and patients receiving warfarin (0.47 nmol/L; P = .009) and (<em>2</em>) a significantly higher mean level of FPA (<em>1</em>.0<em>1</em> nmol/L) than ACA- patients (0.45 nmol/L; P = .0<em>2</em>). When patients with prior thromboembolism were excluded from the analysis, significant differences in the mean levels of F<em>1</em> + <em>2</em> and FPA between ACA+ and ACA- patients were still seen, whereas when patients with prior thromboembolism and/or active disease were excluded from the analysis, a significant difference in the mean level of FPA and a nonsignificant trend in the mean level of F<em>1</em> + <em>2</em> were seen. The results of this study support the hypothesis that the presence of ACA in SLE patients is associated with an ongoing prothrombotic state.

Idarucizumab, a humanised monoclonal antibody <em>fragment</em>, binds dabigatran with high affinity and immediately, completely and sustainably reverses dabigatran-induced changes on blood coagulation. The present analysis focuses on the evaluation of potential procoagulant properties of idarucizumab when administered in the absence of dabigatran. As part of two Phase I studies conducted in healthy Caucasian and Japanese male volunteers, the effect of idarucizumab (8 g as a <em>1</em>-hour [h] infusion and 4 g as a 5-minute [min] infusion) and placebo on calibrated automated thrombography (CAT) was assessed using platelet-poor plasma samples. Measures were made before and <em>1</em>5 min after the end of infusion in Caucasian subjects, as well as pre-dose, <em>1</em>5 min, 4 h and 8 h in Japanese subjects. The levels of the thrombosis markers D-dimer and <em>prothrombin</em> <em>fragment</em> <em>1</em> + <em>2</em> (F<em>1</em>.<em>2</em>) were assessed over time in plasma samples up to 7<em>2</em> h after the end of infusion of idarucizumab and placebo. Idarucizumab had no apparent effect on endogenous thrombin formation as measured by CAT. D-dimer and F<em>1</em>.<em>2</em> levels were highly variable in all dose groups but did not increase when compared with placebo or pre-dose levels. In conclusion, idarucizumab had no effect on endogenous thrombin generation. Additional markers of thrombosis, F<em>1</em>.<em>2</em> and D-dimer, did not differ between placebo and idarucizumab, indicating a lack of procoagulant properties of idarucizumab.

BACKGROUND

Pregnancy is a well-established risk factor for venous thromboembolism, and is associated with a state of hypercoagulability or parameters of thrombin generation. Currently, there is a lack of consensual data on thrombin generation during pregnancy. This study aimed to find a sensitive and specific biological marker of coagulation activation and to identify parameters of thrombin generation.

METHODS

The population included <em>1</em>0<em>1</em> women with uncomplicated pregnancies. The objective of this study was to correlate thrombin generation test (measured at 5pM tissue factor, 4μM lipids and without thrombomodulin), with fibrinogen and markers of blood coagulation activation: D-dimer, <em>prothrombin</em> <em>fragments</em> <em>1</em>+<em>2</em> (F<em>1</em>+<em>2</em>), thrombin-antithrombin complexes (TAT) and fibrin monomer complexes (FMC) in these women. Internal quality control was performed in each set of experiments.

RESULTS

Fibrinogen, D-dimer, F<em>1</em>+<em>2</em>, and TAT concentrations increased significantly throughout pregnancy, and were correlated with term of pregnancy. In our study, thrombin generation seemed to increase early on, and then remained stable throughout normal pregnancy, in contrast with other markers of blood coagulation activation, excepting FMC. The latter are subject to large inter-individual variations, especially during second trimester. No correlation was demonstrated between thrombin generation parameters and other activation markers.

CONCLUSIONS

While markers of coagulation activation significantly increased during pregnancy, thrombin generation increased only early on and remains stable during pregnancy. Finding a sensitive and specific biological marker for vascular pregnancy complications, such as FMC and thrombin generation levels, requires further investigation.

Pigs are often used as animal models in research on blood coagulation and fibrinolysis. The usefulness of the assays applied within this field, and the knowledge of reference intervals are therefore essential and of utmost importance. In the study reported here, we investigated the applicability of commercial human coagulation and fibrinolysis assays for use with porcine plasma. In total, <em>2</em><em>2</em> functional and immunologic assays were applied to plasma obtained from domestic pigs, and the following blood coagulation and fibrinolysis variables were measured: <em>prothrombin</em> time, activated partial thromboplastin time, tissue factor, tissue factor pathway inhibitor, factor VII, protein C, protein S, <em>prothrombin</em> <em>fragment</em> <em>1</em>+<em>2</em>, antithrombin, thrombin-antithrombin complexes, fibrinogen, soluble fibrin, urokinase-type plasminogen activator, plasmin inhibitor, plasminogen activator inhibitor <em>1</em>, and D-dimer. We found that <em>1</em><em>1</em> of <em>1</em><em>2</em> functional assays, but only 3 of <em>1</em>0 immunoassays, were applicable to porcine plasma, and we determined the normal range of these variables. We conclude that human functional assays are useful in porcine plasma, whereas only a few immunologic assays can be used. However, precautions must be taken in interpretation of the results and in extrapolation toward human results because possible differences between porcine and human values can be due to species variations and/or methodologic errors.

In a randomized trial on the effect of dalteparin for 5 weeks after HRS we evaluated hemostatic variables in plasma sampled before and <em>1</em>, 6 and 35 days postoperatively. In <em>2</em><em>1</em>8 patients we found that <em>prothrombin</em> <em>fragment</em> <em>1</em> + <em>2</em> (F<em>1</em> + <em>2</em>), thrombin-antithrombin complexes (TAT), d-dimer and fibrinogen were significantly higher on day 35 as compared with baseline values in the placebo group (P < 0.00<em>1</em> for all). The same pattern was found in the dalteparin group, but with significantly lower values for F<em>1</em> + <em>2</em>, TAT and d-dimer. In patients in the placebo group with venographically proven deep vein thrombosis (DVT) on day 35 (33%), significantly higher values were found for F<em>1</em> + <em>2</em>, TAT and d-dimer than in patients without DVT. Patients in the highest quartile of d-dimer >><em>2</em>850 ng mL-<em>1</em>) had an odds ratio for the presence of DVT of <em>2</em>4.0 when compared with patients in the lowest quartile ((<em>1</em>6<em>2</em>5 ng mL-<em>1</em>). It is concluded that a substantial hypercoagulability is sustained until day 35 after HRS, significantly reduced with prolonged administration of dalteparin.

Pigs are largely used as experimental animal models of thrombosis and for testing the anti thrombotic drug efficacy. Generally experiments are performed on pigs under general anaesthesia and observations can be affected by the anaesthetic drugs used. The effects of a general anaesthetic procedure were checked on pig haemostasis parameters; the pig was pre-anaesthetized with ketamine chloride, then intubated and ventilated with a mixture containing halothane, nitrous oxide and oxygen. Bleeding time, platelet aggregations, coagulation factors, coagulation inhibitors, fibrinolysis parameters and markers of activation of coagulation were determined on 30 Large White pigs before and under this anaesthesia procedure. Compared to human coagulation, pig is characterized by very high levels of factor V, VIII, IX, XI, XII activities, same levels of factor II, fibrinogen, antithrombin III (ATIII), low levels of protein C activities. Thrombin-antithrombin complex (TAT) and tissue plasminogen activator antigen (tPA) values were dispersed. With the reagents used, protein S, <em>prothrombin</em> <em>fragment</em> <em>1</em> + <em>2</em> (F<em>1</em> + <em>2</em>), D Dimers (D-D), plasminogen activator inhibitor (PAi) levels could not be determined. No difference was observed between results obtained before and under anaesthesia, particularly to increase of bleeding time, no modification of platelet aggregations and no activation of coagulation. This anaesthetic procedure does not induce any modification of pig haemostasis and can be used, without side effects, for experimental thrombosis studies in pigs.

BACKGROUND

Abdominal aortic aneurysm (AAA) is associated with hypercoagulability, evidenced by increased markers of coagulation activation, including thrombin-antithrombin complex (TAT), <em>prothrombin</em> <em>fragments</em> <em>1</em> and <em>2</em> (F<em>1</em>+<em>2</em>), and D-dimer. Our aim was to compare the effect of endovascular aneurysm repair (EVAR) and open aneurysm repair (OAR) on changes in coagulation activation markers after intervention.

METHODS

Consecutive patients with AAAs reaching their intervention threshold in a tertiary vascular referral unit in the United Kingdom were invited to participate. The coagulation markers TAT, F<em>1</em>+<em>2</em>, and D-dimer were measured in venous blood collected at baseline and at 5 months after intervention. A forward stepwise multiple linear regression model was used to identify whether treatment by OAR or EVAR had an effect on changes in coagulation factors, independent of significant covariates.

RESULTS

The study included 47 patients (<em>1</em>4 EVAR, 33 OAR; 85% men) who were a median age of 76 years (range, 69.5-80 years). Aortic diameter at intervention was 5.9 cm (range, 5.5-6.8 cm). There were no significant differences in clinical, anthropometric, or hematologic parameters between groups. At baseline, TAT (P = .<em>1</em>3), F<em>1</em>+<em>2</em> (P = .08), and D-dimer (P = .<em>1</em><em>1</em>) were similar in EVAR and OAR patients. Postintervention, there was a significant increase in TAT (3.0 [<em>2</em>.<em>1</em>-6.0] vs 7.<em>2</em> [6.3-8.4] ng/mL; P = .03), F<em>1</em>+<em>2</em> (<em>2</em>4<em>2</em> [<em>1</em>89-3<em>2</em>3] vs 39<em>2</em> [3<em>1</em><em>2</em>-494] ng/mL; P = .003), and D-dimer (457 [336-6<em>1</em>5] vs <em>1</em><em>1</em>97 [840-<em>1</em>509] ng/mL; P = .00<em>2</em>) in the EVAR group. No significant changes were observed after intervention in the OAR group.

CONCLUSIONS

AAA-related hypercoagulability persists after intervention, with increased TAT, F<em>1</em>+<em>2</em>, and D-dimer levels after EVAR. These findings suggest a potential period of increased cardiovascular risk in the postoperative period after EVAR.

BACKGROUND

Traumatic brain injury (TBI) and hemorrhagic shock (HS) are the leading causes of trauma-related deaths. These insults disrupt coagulation and endothelial systems. This study investigated whether previously reported differences in lesion size and brain swelling during normal saline (NS), colloids (Hextend [HEX]), and fresh frozen plasma (FFP) resuscitation are associated with differential effects on coagulation and endothelial systems.

METHODS

We subjected <em>1</em>5 Yorkshire swine to TBI and HS (40% blood volume), and kept in HS for <em>2</em> hours before resuscitation with NS, HEX, or FFP. Markers of endothelial activation (E-selectin, Intercellular adhesion molecule [ICAM]-<em>1</em>), coagulation activation (<em>prothrombin</em> <em>fragment</em> <em>1</em> + <em>2</em>), and natural anticoagulation (activated protein C [aPC]) were determined in serum and brain whole cell lysates.

RESULTS

Serum levels of aPC were greater in the NS group (<em>2</em>03 ± 30 pg/mL) compared with HEX (77 ± <em>2</em>8 pg/mL; P = .0<em>2</em>) and FFP (<em>1</em><em>1</em>0 ± <em>2</em>8 pg/mL; P = .09), as was PF <em>1</em> + <em>2</em> in the brain when compared with FFP (PF <em>1</em> + <em>2</em>, 89 ± 46 vs 37 ± <em>1</em>4 ng/mL; P = .035). Brain E-selectin was greater in the NS group compared with FFP (3.36 ± 0.0<em>2</em> vs 3.3<em>1</em> ± 0.0<em>1</em> ng/mL; P = .0<em>2</em>9). Circulating ICAM-<em>1</em> levels were increased in the NS group (<em>1</em>5<em>1</em> ± 9 ng/mL) compared with the HEX (<em>1</em>00 ± 9 ng/mL; P < .0<em>1</em>) and FFP (<em>1</em>08 ± 9 ng/mL; P = .0<em>1</em>).

CONCLUSIONS

In this clinically realistic large animal model of TBI + HS, NS resuscitation was associated with an early activation of coagulation, natural anticoagulation, and endothelial systems, compared with HEX and FFP.