The impact of a male or female thrombotic family history on contraceptive counseling: a cohort study.

UNLABELLED: Essentials It is unknown if a male or female thrombotic family history influences risk in female relatives. We assessed thrombotic risk in female relatives of male and female patients with thrombosis. A hormonally related female thrombotic family history further increases risk in female relatives. This information could be important in counseling women on contraceptive options. Click to hear Prof. Rosendaal's perspective on venous thrombosis: etiology, pathogenesis, and prognosis SUMMARY: Background Women from thrombophilic families have increased risk of venous thromboembolism (VTE), which increases further during oral contraceptive (COC) use and pregnancy-postpartum. Whether this additional risk differs between relatives of male and female patients, or is different when that female patient had a hormonally related VTE (during COC use/pregnancy), is unknown. Methods One thousand five female relatives of consecutive patients with VTE from a family-based cohort were retrospectively followed for incident VTE from ages 15 to 50, first VTE, or study inclusion. Absolute and relative VTE risks adjusted for factors of patients (sex, age) and relatives (thrombophilia, COC use, pregnancy) were estimated in relatives of female and male patients and in relatives of female patients with and without hormonally related VTE. Results Absolute risk in relatives of female (0.32 [95% confidence interval [CI] 0.23-0.43]) vs. male patients (0.39 [95% CI 0.28-0.53]) was comparable. However, the heterogeneity analysis of risk estimates suggested that in relatives of female vs. male patients, the contribution of pregnancy-postpartum (hazard ratio [HR] 11.6 [95% CI 6.3-21.3] vs. HR6.6 [95% CI 2.8-15.2]) and, to a lesser extent, COC use (HR3.6 [95% CI 1.8-7.1] vs. HR2.7 [95% CI 1.5-5.0]) to the VTE risk differs. Absolute risk was significantly higher in relatives of female patients with hormonally related VTE (0.43 [95% CI 0.3-0.6]) vs. relatives of female patients without hormonally related VTE (0.13 [95% CI 0.05-0.27]), HR3.28 [95% CI 1.5-7.9]). The higher contribution of pregnancy-postpartum and COC use to the VTE risk was mainly observed in relatives of patients with hormonally related VTE. Conclusions These findings suggest that a family history from a female patient, especially when VTE was hormonally related, may further increase VTE risk in her female relatives. This information could be important in counseling women on contraceptive options.

Biomarkers for Prediction of Central Venous Catheter Related-Thrombosis in Patients With Hematological Malignancies.

OBJECTIVE: In a prospective setting, we aimed to find associations between biomarkers of the hemostatic system and the occurrence of central venous catheter (CVC)-related thrombosis in patients with hematological malignancies undergoing intensive chemotherapy. METHODS: The study was conducted between July 2006 and August 2010 at the University Hospital Maastricht, the Netherlands. Consecutive adult patients with hematological malignancies who were going to receive a CVC for intensive chemotherapy were included. The primary end points were (a) symptomatic CVC-related thrombosis and (b) CVC-related infections. Blood samples were taken directly after catheterization, and easy to determine biomarkers (platelet count, leukocyte count, and hemoglobin level) in combination with blood group, factor VIII (FVIII), plasminogen activator inhibitor 1 (PAI-1), activated protein C (APC) resistance, and free protein S antigen were determined. RESULTS: Blood was collected and analyzed from 168 patients. The incidence of symptomatic CVC-related thrombosis was 9%. In univariate analysis, white blood cell count >10.6 × 109/L, mean FVIII activity, and PAI-1 >12.2 IU/mL were found to be associated with the development of symptomatic CVC-related thrombosis. CONCLUSION: Elevated leukocyte count, high PAI-1, and high FVIII were associated with an increased incidence of symptomatic CVC-related thrombosis. We hope in future that simple, easy to determine laboratory tests that reflect the hemostatic and fibrinolytic activity in combination with clinical parameters may help to identify hematological patients at highest risk of CVC-related thrombosis and help to tailor the management of thromboprophylaxis in hematological patients undergoing CVC placement.

Concentrated citrate locking in order to reduce the long-term complications of central venous catheters: a randomized controlled trial in patients with hematological malignancies.

PURPOSE AND METHODS: Central venous catheter (CVC)-related thrombosis and infections are frequently occurring complications in patients with hematological malignancies. At present, heparin is most often used as a locking solution. Trisodium citrate (TSC) had been shown to be a very effective antimicrobial catheter locking in hemodialysis patients. We performed a prospective randomized phase III multicenter trial to determine the efficacy of TSC as a locking solution compared to heparin in preventing CVC-related thrombosis and infections in patients with hematological malignancies. RESULTS: Thirty-four episodes of CVC-related bloodstream infections (CVC-BSI) occurred in the 108 patients who were randomized to locking with heparin compared with 35 episodes in the 99 patients who were randomized to locking with TSC (P = 0.654). We did find seven times more CVC-BSI with gram-negative rods in CVCs locked with heparin (P = 0.041). The cumulative incidence of symptomatic thrombosis was 10% in the heparin group and 5% in the TSC group (hazard ratio 0.525; 95% confidence interval 0.182-1.512). CONCLUSION: This study shows that locking with TSC in patients with hematological malignancies significantly reduced the incidence of CVC-BSI with gram-negative rods. However, the incidence of CVC-BSI with coagulase-negative staphylococcus or CVC-related thrombosis was not reduced by TSC locking.

Effect of low-dose supplements of menaquinone-7 (vitamin K2 ) on the stability of oral anticoagulant treatment: dose-response relationship in healthy volunteers.

BACKGROUND AND OBJECTIVE: Despite the worldwide use of vitamin K antagonists (VKAs), there is limited knowledge of the influence of dietary vitamin K on anticoagulation control. In view of the increasing nutraceutical availability of menaquinone-7 (MK-7; vitamin K2 ) and its promotion for bone and cardiovascular health, it is important to determine the posology for the interference of supplemental MK-7 with VKA therapy. PATIENTS: Eighteen healthy men and women were anticoagulated for 4 weeks with acenocoumarol, and 15 of them attained a target International Normalized Ratio (INR) of 2.0. In the six subsequent weeks, subjects were given increasing doses of MK-7 (10, 20 and 45 µg day(-1) ) while continuing acenocoumarol treatment at established individual doses. RESULTS: Apart from the INR, acenocoumarol treatment significantly increased the levels of uncarboxylated factor II (ucFII), uncarboxylated osteocalcin (ucOC), and desphospho-uncarboxylated matrix Gla-protein (dp-ucMGP), and decreased endogenous thrombin generation (ETP). A daily intake of 45 µg of MK-7 significantly decreased the group mean values of both the INR and ucFII by ~ 40%. Daily intakes of 10 and 20 µg of MK-7 were independently judged by two hematologists to cause a clinically relevant lowering of the INR in at least 40% and 60% of subjects, respectively, and to significantly increase ETP by ~ 20% and ~ 30%, respectively. Circulating ucOC and dp-ucMGP were not affected by MK-7 intake. CONCLUSIONS: MK-7 supplementation at doses as low as 10 µg (lower than the usual retail dose of 45 µg) significantly influenced anticoagulation sensitivity in some individuals. Hence, the use of MK-7 supplements needs to be avoided in patients receiving VKA therapy.

Perioperative dilutional coagulopathy treated with fresh frozen plasma and fibrinogen concentrate: a prospective randomized intervention trial.

BACKGROUND AND OBJECTIVES: Treatment of dilutional coagulopathy by transfusing fresh frozen plasma (FFP) remains sub-optimal. We hypothesized that partial replacement of transfused FFP by fibrinogen concentrate results in improved coagulant activity and haemostasis. This was tested in a controlled clinical intervention trial with patients experiencing massive bleeding during major surgery. METHODS: Patients undergoing major elective surgery were treated according to current protocols. When transfusion with FFP was required, patients were randomized as follows: group A received 4 units FFP and group B received 2 units FFP plus 2 g fibrinogen concentrate. Blood samples were taken before and after the intervention. Analysts were blinded to the treatment type. RESULTS: Group A (B) consisted of 21 (22) patients, in 16 (17) of whom bleeding stopped after intervention. Plasma fibrinogen increased significantly more in group B (0·57 g/l) than in group A (0·05 g/l). However, levels of prothrombin and factors VIII, IX and X increased more in group A than in group B. Rotational thromboelastometry (ROTEM) of whole blood and plasma revealed improved fibrin clot formation in group B but not in group A. Thrombin generation [calibrated automated thrombogram (CAT)] in plasma increased more in group A. Principal parameters determining whole-blood thromboelastometry were the fibrinogen level and platelet count. In vitro addition of fibrinogen and prothrombin complex concentrate to pre-intervention samples restored both ROTEM and CAT parameters. CONCLUSIONS: Partial replacement of transfused FFP by fibrinogen increases fibrin clot formation at the expense of less improved thrombin generation. Coagulation factors other than fibrinogen alone are required for full restoration of haemostasis.

Differential protein expression in serum of abdominal aortic aneurysm patients - a proteomic approach.

OBJECTIVE: The aim of the study is to investigate the differential expression of proteins in serum of abdominal aortic aneurysm (AAA) patients in relation to aneurysm size (D(max)) and progression. METHODS: Two-dimensional differential in-gel electrophoresis (2D-DIGE) together with tandem mass spectrometry (MS/MS) was used to analyse the serum proteome from patients with small (D(max) 30-54 mm) AAA, either stable (increase D(max) <5 mm year⁻¹; n = 8) or progressive (increase D(max) ≥5 mm year⁻¹; n = 8), and large (D(max) ≥ 55 mm; n = 8) AAA. The identified proteins were quantitatively validated in a larger population (n = 80). RESULTS: Several proteins were differentially expressed in serum of small stable, small progressive and large AAA. Three validated proteins (immunoglobulin G (IgG), α1-antitrypsin (α1-AT) and Factor XII activity) showed strong correlation with D(max). Size combined with either Factor XII activity or α1-antitrypsin had minimal effect on the prognostic value in predicting aneurysm progression compared with size alone (area under the curve (AUC), 0.85; 95% confidence interval (CI), 0.73-0.97; p < 0.001 and AUC, 0.85; 95% CI, 0.72-0.98; p < 0.001 vs. AUC, 0.83; 95% CI, 0.71-0.96; p < 0.001, respectively). CONCLUSION: The present study indicates that both Factor XII and α1-antitrypsin are found in increased amounts in the serum of patients with expanding AAA. However, combination of either Factor XII or α1-antitrypsin with aneurysm diameter had little effect on prediction of aneurysm progression versus diameter alone.

Risk factors of arterial cardiovascular complications in patients with prior venous thromboembolism.

BACKGROUND: The effect of cardiovascular risk factors (CVRs) and thrombophilic defects on the risk of arterial cardiovascular complications in patients with prior venous thromboembolism (VTE) is unclear. OBJECTIVE: We investigated whether the risk of arterial cardiovascular complications is increased after VTE and whether CVRs and thrombophilic defects influence this risk. METHODS: Subjects were selected from three family cohorts of probands with VTE or arterial cardiovascular complication before the age of 50 and thrombophilic defects (i.e. hyperhomocysteinaemia, prothrombin G20210A or elevated FVIII). For this analysis, probands with arterial cardiovascular complications before inclusion and their relatives as well as relatives without the studied thrombophilic defects were excluded. We calculated the incidence of arterial cardiovascular complications (e.g. myocardial infarction, ischaemic stroke, transient ischaemic attack or peripheral arterial disease) in subjects with and without VTE and adjusted the relative risk for at least one CVR, two or more thrombophilic defects and quintiles of a propensity score (considering risk factors conditional to VTE history). RESULTS: 861 subjects were included, of whom 399 had experienced VTE before inclusion. Twelve arterial cardiovascular complications occurred in subjects with and nine in subjects without VTE history. Hence the annual incidence was 1.0 (95% CI 0.5 to 1.7) and 0.7 (0.3 to 1.2) in subjects with and without VTE (RR 1.5, 0.6 to 3.6). Adjusting for possible confounders did not change this relative risk. CONCLUSION: The mildly elevated risk of arterial cardiovascular complications in patients with prior VTE appears to be independent of cardiovascular risk factors and thrombophilic defects.

Thrombin generation in patients with a first acute myocardial infarction.

BACKGROUND: Despite improved treatment options, myocardial infarction is still an important cause of morbidity and mortality. One of the contributing mechanisms in the acute myocardial infarction (AMI) is plasma hypercoagulability. METHODS: We investigated hypercoagulability in 135 (first) patients with AMI using thrombin generation (TG) testing. TG testing was performed in plasmas, drawn upon admission and before medication administration, and subsequently after 4 days, 3 and 6 months. Further, we evaluated determinants of thrombin generation using multiple regression analysis of major coagulation proteins and inhibitors. Admission TG results were also related to 1-year outcome: cardiovascular death, recurrent myocardial infarction, a second coronary intervention [percutaneous coronary intervention (PCI) or coronary artery bypass grafting (CABG)] and ischemic stroke. RESULTS: At day 0, the TG parameters peak height, endogenous thrombin potential (ETP) and lag time were increased compared with a reference population. Peak height and lag time stayed persistently increased in patients. The lowest half of the ETP values was statistically not significantly associated with an occurrence of endpoints. The lowest half of the ETP values combined with the upper half of the D-dimer values were associated with endpoints; odds ratio 5.8 (1.1-30.7). Tissue factor pathway inhibitor (TFPI) seems to be an important determinant of TG in AMI and healthy persons. CONCLUSIONS: TG reflects acute hypercoagulability during AMI and partly also in the 6-month period after the acute event. TG shows a trend of an inverse association with risk of recurrent ischemic cardiovascular complications. Unraveling mechanisms in TG might improve our understanding of the pathophysiology of AMI and direct future improvements in medical care.

[Old and new anticoagulants. Antidotes and measures for acute hemorrhaging and urgent interventions]. / Alte und neue Gerinnungshemmer. Antidota und Massnahmen bei akuter Blutung sowie dringenden Eingriffen.

Anticoagulation medications are frequently used for primary and secondary treatment of several thrombo-embolic disorders. An important side effect of all anticoagulants is hemorrhagic diathesis which necessitates acute treatment, ideally using medicinal therapy with an antidote. Much experience has been gained in treating bleeding while on traditional anticoagulants, such as heparins and vitamin K antagonists by the use of antagonists. A multitude of factor-specific anticoagulants have recently been introduced or will soon receive approval. With this new generation of anticoagulants no valid laboratory parameters or effective antagonists are presently available. Due to a lack of adequate studies regarding acute treatment this can at present only be carried out on a symptomatic basis.

Impaired thrombin generation and fibrin clot formation in patients with dilutional coagulopathy during major surgery.

Patients subjected to haemodilution during surgery are at increased risk of bleeding. We hypothesised that, in the acquired dilutional coagulopathy, insufficient haemostasis is due to either insufficient thrombin generation or insufficient fibrin clot formation. In tissue factor-activated plasmas from patients with coagulation deficiency, we measured time curves of thrombin generation and fibrin clot formation (thromboelastography). Investigated were in study A: 10 patients treated with vitamin K antagonist and five healthy subjects; in study B: 30 patients undergoing cardiopulmonary bypass (CPB) surgery and infused with on average 2,000 ml crystalloids and colloids (no major bleeding); in study C: 58 patients undergoing major general surgery, and transfused with >5,000 ml crystalloids, colloids and red cell concentrates, who experienced major bleeding and were post-transfused with fresh frozen plasma. The treatment with vitamin K antagonist led to a progressive reduction in thrombin generation but not fibrin clot formation. In CPB patients, plasma factor levels post-surgery were 53-60% of normal. This was accompanied by moderate reduction in both haemostatic processes. In plasmas from patients undergoing major surgery, factor levels were 38-41% of normal, and these levels increased after plasma transfusion. Taking preset thresholds for normal thrombin generation and fibrin clot formation, at least one of these processes was low in 88-93% of the patients with (persistent) bleeding, but only in 40-53% of the patients without bleeding. In conclusion, the ability of thrombin generation and fibrin clot formation is independently reduced in acquired dilutional coagulopathy, while minimal levels of both are required for adequate haemostasis.

Active site inhibited factor VIIa attenuates myocardial ischemia/reperfusion injury in mice.

BACKGROUND: Inhibition of specific coagulation pathways such as the factor VIIa-tissue factor complex has been shown to attenuate ischemia/reperfusion (I/R) injury, but the cellular mechanisms have not been explored. OBJECTIVES: To determine the cellular mechanisms involved in the working mechanism of active site inhibited factor VIIa (ASIS) in the protection against myocardial I/R injury. METHODS: We investigated the effects of a specific mouse recombinant in a mouse model of myocardial I/R injury. One hour of ischemia was followed by 2, 6 or 24 h of reperfusion. Mouse ASIS or placebo was administered before and after induction of reperfusion. RESULTS: ASIS administration reduced myocardial I/R injury by more than 40% at three reperfusion times. Multiplex ligation dependent probe amplification (MLPA) analysis showed reduced mRNA expression in the ischemic myocardium of CD14, TLR-4, interleukin-1 (IL-1) receptor-associated kinase (IRAK) and IkappaBalpha upon ASIS administration, indicative of inhibition of toll-like receptor-4 (TLR-4) and subsequent nuclear factor-kappaB (NF-kappaB) mediated cell signaling. Levels of nuclear activated NF-kappaB and proteins influenced by the NF-kappaB pathway including tissue factor (TF) and IL-6 that were increased after I/R, were attenuated upon ASIS administration. After 6 and 24 h of reperfusion, neutrophil infiltration into the area of infarction was decreased upon ASIS administration. There was, however, no evidence of an effect of ASIS on apoptosis (Tunel staining and MLPA analysis). CONCLUSIONS: We conclude that the diminished amount of myocardial I/R injury after ASIS administration is primarily due to attenuated inflammation-related lethal I/R injury, probably mediated through the NF-kappaB mechanism.

Coagulation factors and the protein C system as determinants of thrombin generation in a normal population.

BACKGROUND: Thrombin generation is a powerful tool to probe overall plasma coagulability. OBJECTIVE: To determine which plasma factors influence the various parameters of the thrombin generation curve, for example lag time, peak height and endogenous thrombin potential (ETP), under different experimental conditions. PATIENTS AND METHODS: Plasma levels of coagulation factors and inhibitors, as well as thrombin generation at 1 pm tissue factor (TF) +/- thrombomodulin (TM) and at 13.6 pm TF +/- activated protein C (APC), were determined in plasma from 140 healthy individuals. Data were analysed by multiple regression models. RESULTS: Thrombin generation increased with age and was higher in females than in males. Under all conditions, the lag time was mainly dependent on the levels of free tissue factor pathway inhibitor (TFPI), free protein S (PS), factor VII (FVII), FIX and fibrinogen. The major determinants of thrombin generation (ETP and peak height) at 1 pm TF were fibrinogen, FXII (despite inhibition of contact activation), free TFPI and antithrombin (AT), both in the absence and in the presence of TM. Thrombin generation in the presence of TM was also dependent on protein C levels. At 13.6 pm TF, thrombin generation was determined by prothrombin, AT, fibrinogen, free TFPI and FV levels in the absence of APC, and by free TFPI, free PS and FX levels in the presence of APC. CONCLUSIONS: The lag time, ETP and peak height of thrombin generation depend on the levels of multiple coagulation factors and inhibitors. The specific assay determinants vary with the experimental conditions.

The plasma kallikrein-kinin system and risk of cardiovascular disease in men.

BACKGROUND: The plasma kallikrein-kinin system (PKKS) has been implicated in cardiovascular disease, but activation of the PKKS has not been directly probed in individuals at risk of coronary heart disease (CHD) or stroke. OBJECTIVE: To determine the involvement of the PKKS, including factor XI, in cardiovascular disease occurring in a nested case-control study from the Second Northwick Park Heart Study (NPHS-II). METHODS AND RESULTS: After a median follow-up of 10.7 years, 287 cases of CHD and stroke had been recorded and 542 age-matched controls were selected. When FXIIa-C1 esterase inhibitor (C1-inhibitor) concentrations were divided into tertiles (lowest tertile as reference), the odds ratios (ORs) at 95% CIs for CHD were 0.52 (0.34-0.80) in the middle tertile and 0.73 (0.49-1.09) in the highest tertile (P = 0.01 for the overall difference; P = 0.01 for CHD and stroke combined). For kallikrein-C1-inhibitor complexes, the ORs for stroke were 0.29 (0.12-0.72) and 0.67 (0.30-1.52) in the middle and high tertiles, respectively (P = 0.02). FXIIa-C1-inhibitor and kallikrein-C1-inhibitor complexes were negatively related to smoking and fibrinogen (P < 0.005). FXIa-inhibitor complexes correlated strongly with FXIIa-inhibitor complexes. CONCLUSIONS: Lower levels of inhibitory complexes of the PKKS enzymes and particularly of FXIIa contribute to the risk of CHD and stroke in middle-aged men. This observation supports the involvement of the PKKS in atherothrombosis.

Outcome of the subsequent pregnancy after a first loss in women with the factor V Leiden or prothrombin 20210A mutations.

BACKGROUND: The factor V Leiden (FVL) and prothrombin 20210A (PTm) mutations are associated with single late pregnancy loss and recurrent early pregnancy loss. The prognosis after an initial loss in women with thrombophilia is uncertain. OBJECTIVE: To assess the pregnancy outcome of the second pregnancy after a first loss in women with and without either FVL or PTm mutations. METHODS: We selected women with a first pregnancy loss out of two family cohorts of first degree relatives of probands with FVL or PTm mutations and a history of documented venous thromboembolism or premature atherosclerosis. RESULTS: Ninety-three women had had a first pregnancy loss and became pregnant a second time. Their risk of loss of the subsequent pregnancy was higher than in 825 women with a successful first pregnancy [25 vs. 12%, relative risk (RR) 2.0, 95% CI 1.4-3.0]. The live birth rate of the second pregnancy after an early first loss ( 12 weeks), the live birth rates were 68% (95% CI 46-85) and 80% (95% CI 49-94) for carriers and non-carriers, respectively (RR 0.9, 95% CI 0.5-1.3). CONCLUSIONS: Women with a first pregnancy loss have a 2-fold increased risk of loss of the subsequent pregnancy, regardless of their carrier status. More importantly, the outcome of the second pregnancy is rather favorable in absolute terms, even for those with thrombophilia and a late loss, which raises concern regarding the risks and presumed benefits of anticoagulant therapy in these women.

Changes in fibrinolytic activity after angiotensin II receptor blockade in therapy-resistant hypertensive patients.

BACKGROUND: In hypertensive patients, the activated renin-angiotensin system induces a prothrombotic state resulting from imbalance between coagulation and fibrinolysis. Although blood pressure cannot be regulated in therapy-resistant hypertensive patients, they may still be responsive to medication that attenuates the renin-angiotensin system. OBJECTIVE: our objective was to study possible attenuating properties of angiotensin II type 1 receptor blockers (AT1RBs) on the prothrombotic state in therapy-resistant hypertensive patients, focusing on parameters of fibrinolysis and coagulation. METHODS: Fourteen therapy-resistant hypertensive patients received AT1RB eprosartan infusion (45 and 150 microg kg(-1)) (study group), and 33 therapy-resistant hypertensive patients received saline (0.9%) infusion (control group) prior to renal angiography. Baseline values of parameters of coagulation and fibrinolysis were set at 1.00, and relative changes were calculated. RESULTS: Plasminogen activator inhibitor type 1 (PAI-1) antigen showed non-significant decreases in both the study group (arterial 1.00-0.45, venous 1.00-0.42) and control group (arterial 1.00-0.84, venous 1.00-0.88). PAI-1 activity significantly decreased in the study group (arterial 1.00-0.72, venous 1.00-0.71) and control group (arterial 1.00-0.83, venous 1.00-0.94). In the study group, tissue-type plasminogen activator (t-PA) antigen decreased significantly (arterial 1.00-0.62, venous 1.00-0.67), whereas t-PA activity significantly increased (arterial 1.00-6.15, venous 1.00-2.66). In the control group, t-PA antigen remained unchanged. No changes were observed in blood pressure during and after infusion of eprosartan. CONCLUSION: Therapy-resistant hypertensive patients show beneficial changes in fibrinolytic activity after infusion of a non-pressor dose of AT1RB.

Soluble tissue factor is a candidate marker for progression of microvascular disease in patients with Type 2 diabetes.

OBJECTIVE: To determine the relationship between abnormalities in blood coagulation and prevalent or incident cardiovascular complications in Type 2 diabetes. DESIGN AND METHODS: Prospective cohort study of 128 patients with Type 2 diabetes in whom blood samples were collected at baseline and after 1 year of follow-up. All cardiovascular complications at baseline and follow-up were recorded. Forty-three healthy, age-matched subjects served as a control group. RESULTS: Logistic analysis revealed an independent relationship between soluble tissue factor (TF) and microvascular disease [per pg mL(-1) TF: Exp(B) = 1.008; CI(95%)1.002-1.014], or neurogenic disease [Exp(B) = 1.006; CI(95%)1.001-1.011]. The highest levels of soluble TF were observed in patients with microvascular and neurogenic disease (P < 0.001). Patients with Type 2 diabetes having a soluble TF concentration >300 pg mL(-1) are at a 15-fold higher risk for the presence of microvascular disease and at a 10-fold higher risk for the presence of neurogenic disease compared with the patients with concentrations below 100 pg mL(-1). Soluble TF was correlated with tissue type plasminogen activator, von Willebrand factor antigen, systolic blood pressure and age. Levels of F1' + 2, D-dimer, FVIII activity, t-PA and vWFag were not different among patients with micro-, macro- or neurogenic complications compared with patients without those complications. Forty-eight new micro-, macro- and/or neurogenic complications were diagnosed after 1 year follow-up. With the exception of higher F1 + 2 levels after 1 year all other markers remained unchanged. A trend toward higher soluble TF levels was observed in patients with new microvascular events (P = 0.056). CONCLUSIONS: Soluble TF is associated with existing microvascular and neurogenic complications in patients with Type 2 diabetes and is a candidate marker for progression of microvascular disease.