The effect of beta-receptor blockade on factor VIII levels and thrombin generation in patients with venous thromboembolism

High factor VIII (FVIII) is a risk factor for venous thromboembolism (VTE).The pathomechanism by which high FVIII leads to an increased risk of VTE is unknown. Physical activity and infusion of adrenalin provoke a rise in FVIII, which can be blocked by a nonselective beta-blockade. We tested the hypothesis that in patients with a VTE beta-blockade decreases FVIII and inhibits coagulation activation. 17 male patients with high FVIII (> 170 IU/dL, n = 7) or low FVIII (<150 IU/dL, n = 10) and a history of VTE received 40 mg of propranolol thrice daily for 14 days. FVIII and vasopressin levels were measured before and during propranolol intake and 28 days thereafter. At the same time points, haemostatic system activation was investigated by measuring prothrombin fragment f1.2 (f1.2) and thrombin antithrombin complexes (TAT) in venous blood and in blood emerging from a skin incision (shed blood). The mean FVIII level before propranolol was 192 IU/dL and 115 IU/dL in patients with high and low FVIII, respectively. During and 28 days after propranolol, no significant change in FVIII was seen in both groups. Changes in f1.2 and TAT were not detectable in either venous blood or in shed blood. beta-receptor blockade did not lower FVIII or inhibit haemostatic system activation in patients with VTE and persistently high FVIII. Administration of propranolol cannot be recommended as secondary thromboprophylaxis in patients with high FVIII.     

Elevated factor VIII is a risk factor for idiopathic venous thromboembolism in Canada - is it necessary to define a new upper reference range for factor VIII?

Previous studies suggest elevated factor VIII is a common, independent risk factor for venous thromboembolism (VTE); however, these studies included secondary and idiopathic VTE. We sought to explore the association between elevated factor VIII and VTE in Canadian patients with idiopathic thrombosis, and confirm the current upper factor VIII reference range was appropriate. We enrolled 300 consecutive patients with idiopathic VTE who were matched to friend controls by age, sex and ethnicity. Factor VIII levels were measured and compared between cases and controls. The optimal cut-off value to designate factor VIII levels as elevated was determined using a variety of methods. The optimal upper cut-off value for factor VIII levels was 270 IU/dl. In the logistic regression analysis, cases were more likely to have elevated factor VIII levels (OR:8.76), as were females (OR:1.93) and older subjects (OR: 1.05). Factor VIII cutoffs for a 95% specificity by age were 238 IU/dl for subjects <40 years, 248 IU/dl age 40-55 years, 261 IU/dl age 56-70 years, and 313 IU/dl age >70. Our findings confirm that elevated factor VIII is associated with an increased risk of idiopathic VTE. In our patients and matched controls, the current upper limit of normal (150 IU/dl) for factor VIII is not of clinical use. We propose that the upper limit be increased to 270 IU/dl or individual labs should establish their upper limit if they wish their assays to be discriminatory in patients with VTE. Age specific cut-offs may be clinically relevant.     

The ABO blood group genotype and factor VIII levels as independent risk factors for venous thromboembolism

Factor VIII (FVIII), von Willebrand factor (vWF) and the ABO blood groups have been associated with thrombosis. The ABO locus has functional effects on vWF and FVIII levels and is genetically correlated with FVIII, vWF and thrombosis. We carried out a case-control study to assess the role of FVIII, vWF and ABO types on thrombotic risk. We analyzed 250 patients with venous thrombosis and 250 unrelated controls. FVIII, vWF and other factors related to thrombophilia were measured, ABO groups were analyzed by genotyping. FVIII and vWF were higher in non-O individuals. Group O was more frequent in the controls (44.3% v 23.3%; difference 21.1%; 95% CI: 13.0-29.3%) and Group A in patients (59.2% v. 41.5%; difference 17.7%, 95% CI: 9.1-26.4%). Individuals carrying the A1 allele had a higher risk of thrombosis (OR 2.6; 95% CI, 1.8-3.8). The risk attributed to vWF disappeared after adjusting for the ABO group. Patients with FVIII above the 90th percentile had a high thrombotic risk (adjusted OR 3.7; 95% CI, 2.1-6.5), and a high risk of recurrence (OR 2.3; 95% CI: 1.3-4.1). In conclusion, high FVIII levels and non-O blood groups, likely those with the A1 allele, are independent risk factors for venous thromboembolism and should be considered in evaluating of thrombophilia.     

An abnormal ProC Global test result is associated with an increased risk of venous thromboembolism independent of test sensitivity for protein C pathway abnormalities

The ProC Global assay is a clotting assay primarily developed to globally evaluate the functionality of the protein C (PC) pathway. It was shown to lack both sensitivity and specificity for PC pathway abnormalities, i.e. factor V Leiden mutation, PC and PS deficiency. The hypothesis that an abnormal test result could be associated with venous thromboembolism (VTE) was evaluated in a case-control study. The proportion of reduced response was significantly higher in cases than in controls [n = 71/139 (51.1%) vs. n = 28/147 (19.0%); p < 0.0001] and the same applied after exclusion of those subjects with any PC pathway abnormality [n = 53/119 (44.5%) vs. n = 25/143 (17.5%); p < 0.0001]. An abnormal ProC Global assay result was significantly associated with thrombosis both in the whole population (odds ratio [OR]=4.44, 95% confidence interval [CI]=2.61-7.53) and in those subjects without any PC pathway abnormality (OR = 3.70, 95%CI = 2.16-6.66). The ProC Global assay result was significantly lower in cases with idiopathic VTE than in those with secondary VTE (p < 0.0001). No significant difference was observed when cases were classified according to the presence or absence of recurrent episodes. Moreover, a reduced response was found to be associated with VTE both in subjects with normal or elevated factor VIII (FVIII) level. In vitro, FVIII was found to play a critical role in the ProC Global assay result as suggested by the significant trend toward decreasing response with increasing FVIII levels. In conclusion, our results suggest that an abnormal ProC Global assay result is associated with an increased risk of VTE independently of its sensitivity for PC pathway abnormalities.     

Low density lipoprotein receptor-related protein polymorphisms are not risk factors for venous thromboembolism

Low-density lipoprotein receptor-related protein is a receptor involved in factor VIII catabolism. In spite of elevated factor VIII coagulant activity levels being a well-established independent risk factor for venous thrombosis, the origin of this abnormality is unknown. In this study, we investigated the role of polymorphisms C220T (exon 22), A775P (exon 14) and D2080N (exon 39) in the gene coding for this receptor in 249 patients (100 males/149 female, mean age 36.5 SD:11 years) with venous thromboembolism and 366 controls (155 male/211 females, mean age 38 SD:11 years ) matched by age and gender. The polymorphisms C220T (CT OR: 0.9, 95%CI: 0.6-1.2; TT OR: 1.0, 95%CI: 0.6-1.5) and D2080N (OR: 0.8, 95%CI: 0.3-2.4) were not associated to thrombosis susceptibility while the polymorphism A775P was identified in neither patients or controls. D2080N polymorphism was associated with factor VIII and von Willebrand factor levels, in the control group. Heterozygous individuals (DN), compared with homozygotes individuals (DD), presented lower levels of factor VIII (mean difference: 42.3 IU/dL, 95%CI: 5.7-78.9) and von Willebrand factor (mean difference: 34.8 IU/dL, 95%CI: 4.9-64.6). In conclusion, we demonstrated an association between D2080N polymorphism with factor VIII and von Willebrand factor levels in Brazilian normal individuals. However, none of the three polymorphisms in low-density lipoprotein receptor related protein gene were related to venous thrombosis risk in these patients.     

D-dimer and factor VIII are independent risk factors for recurrence after anticoagulation withdrawal for a first idiopathic deep vein thrombosis

Background and objectives: To assess the predictive value of D-dimer (D-d) and Factor VIII (FVIII) in combination for recurrent venous thromboembolism (VTE) after vitamin K antagonist (VKA) therapy suspension. Design and methods: Consecutive outpatients with a first episode of idiopathic proximal deep vein thrombosis of the lower limbs were enrolled on the day of VKA suspension. After 30+/-10 days, D-d (cut-off value: 500 ng/mL), chromogenic FVIII activity and inherited thrombophilia were determined. Follow-up was 2 years. Results: Overall recurrence rate was 16.4% (55/336; 95% CI:13-21%). The multivariate hazard ratio (HR) for recurrence was 2.45 (95% CI: 1.24-4.99) for abnormal D-d and 2.76 (95% CI:1.57-4.85) for FVIII above the 75th percentile (2.42 U/mL) after adjustment for age, sex, thrombophilia, VKA duration and residual venous obstruction. When compared with normal D-d and FVIII, the multivariate HR was 4.5 (95% CI: 1.7-12.2) for normal D-d with FVIII above 2.42 U/mL and 2.7 (95% CI: 1.2-6.6) and 7.1 (95% CI:2.8-17.6) for abnormal D-d with FVIII, respectively, below and above 2.42 U/mL. Interpretation and conclusions: D-d and FVIII at 30+/-10 days after VKA withdrawal are independent risk factors for recurrent VTE.     

Elevated factor VIII increases the risk of cerebral venous thrombosis: a case–control study

Background

Elevated factor VIII (FVIII) is a risk factor for leg-vein thrombosis and pulmonary embolism. We assessed whether elevated FVIII is also a risk factor for cerebral venous thrombosis (CVT).

Methods

We performed a matched case–control study. We assessed patients with CVT, as cases, admitted between July 2006 and December 2016. The controls were healthy hospital-staff employees matched for age (within 5 years) and sex. FVIII activity was measured at least 3 months after CVT diagnosis. Elevated FVIII was defined as activity?>?150 IU/dl. We used logistic regression analysis, adjusting for age and sex.

Results

We included 116 cases and 116 controls (85% women for both groups). Mean age was 40 (SD 11) and 41 (SD 11) years for cases and controls, respectively. Median time between CVT diagnosis and blood collection was 18 months (IQR 7–39 months). Cases more often had elevated FVIII as compared to controls (83.6 vs 28.4%, p?<?0.001). After adjustment, elevated FVIII was associated with a 15-fold increased risk of CVT (OR 15.3, 95% CI 7.8–30.1). Stratification by sex showed a stronger association in men (OR 22.8, 95% CI 2.8–184.3) than in women (OR 14.7, 95% CI 7.2–30.2).

Conclusion

Elevated FVIII occurs frequently in patients with CVT and is a strong risk factor for this condition.

     

Venous thrombosis following the use of intermediate purity FVIII concentrate to treat patients with von Willebrand's disease

We describe four patients with von Willebrand's disease (VWD) who experienced venous thrombosis after treatment with an intermediate purity factor VIII (FVIII) concentrate (Haemate P3) was used to cover invasive or surgical procedures. Most patients had additional risk factors for venous thromboembolism (VTE) and it is difficult to be certain of the contribution of the concentrate to the VTE. In view of the recognised association between high factor VIII activity (FVIII:C) levels and VTE there is a physiological basis for this complication and it is important to consider this when administering FVIII containing concentrates to VWD patients.     

Factor VIII levels and the risk of pre-eclampsia, HELLP syndrome, pregnancy related hypertension and severe intrauterine growth retardation

OBJECTIVE: Recently, acquired as well as genetic prothrombotic factors are associated with thrombotic events. These factors have also been related to conditions of uteroplacental insufficiency such as pre-eclampsia, HELLP syndrome and severe intrauterine growth restriction (IUGR). The aim of this study was to determine whether elevated factor VIII levels are associated with uteroplacental insufficiency, in particular pre-eclampsia, HELLP syndrome or pregnancy-induced hypertension and intrauterine growth retardation. METHODS: Plasma samples of 75 women with a history of pregnancy complicated by pre-eclampsia, HELLP syndrome, pregnancy induced hypertension or intrauterine growth restriction were tested for factor VIII:C (FVIII:C) levels at a minimum of 10 weeks post-partum. Laboratory results were compared to factor VIII:C levels found in a healthy control group of 272 women. RESULTS: Mean factor VIII:C levels were similar at 123 IU/dl in both the patient group and the controls. In a logistic regression model, after adjusting for age and blood group, no effect of factor VIII:C levels on the risk of pregnancy complications was observed, with the exception of IUGR with (OR 2.9, CI 1.0-8.7) or without hypertension (OR 2.0, CI 0.7-6.4). CONCLUSION: If the elevated level of factor VIII would be the sole factor responsible for the increased risk observed, one would expect to find an effect of blood group on risk as well (blood group being an important determinant of FVIII:C). While no such effect could be shown a causal relationship between elevated levels of factor VIII and conditions of uteroplacental insufficiency such as pre-eclampsia, HELLP syndrome, pregnancy-induced hypertension and IUGR is not very likely.     

The acute phase reaction explains only a part of initially elevated factor VIII:C levels: a prospective cohort study in patients with venous thrombosis

We determined in a prospective cohort of patients treated with vitamin K antagonists for venous thrombosis, the course of factor VIII (FVIII:C), C-reactive protein (CRP) and fibrinogen levels, to assess the influence of the acute phase reaction on FVIII:C levels. Second, we hypothesized that patients with preceding infectious symptoms might have higher levels of FVIII:C at baseline than patients without those.We included 75 patients. Blood was sampled at baseline, once during treatment (t = 1) and at the end of treatment (t = 2). Mean levels of FVIII:C were 207, 186 and 175 IU/dL (p for trend 0.003) at baseline, t = 1 and t = 2 respectively. Eight-eight percent of patients had an elevated FVIII:C at baseline, 75% at t = 1 and 72% at t = 2 (p for trend 0.045). Mean levels of FVIII:C were not different in patients with or without preceding infectious symptoms (206 versus 205 IU/dL respectively). A baseline CRP level below 62 mg/L could best distinguish between patients who will keep an elevated FVIII:C and those who will drop below 150 IU/dL.We conclude that FVIII:C levels are partially influenced by the acute phase reaction, especially in patients who keep a persistent elevated FVIII:C during treatment.Preceding infectious symptoms did not influence baseline FVIII:C levels.     

Hereditary and acquired thrombophilia in patients with upper extremity deep-vein thrombosis. Results from the MAISTHRO registry

The prevalence of coagulation disorders in patients with upper extremity deep-vein thrombosis (UE-DVT) is unknown due to only a few observational studies of limited size reporting varying results. Therefore, we aimed to evaluate the prevalence of thrombophilia in patients with UE-DVT compared to patients with lower extremity deep vein thrombosis (LE-DVT). One hundred fifty consecutive patients (15 to 91 years of age) with UE-DVT were recruited from the MAISTHRO (MAin-ISar-THROmbosis) registry. Three hundred LE-DVT patients matched for gender and age served as controls. Thrombophilia screening included tests for the factor V Leiden mutation, the prothrombin G20210A mutation, antiphospholipid antibodies and factor VIII (FVIII), protein C, protein S and antithrombin activities. At least one thrombophilia was present in 34.2% of UE-DVT and 39.2% in UE-DVT that was unrelated to venous catheters relative to 55.3% in LE-DVT patients (p < 0.001). In particular, a persistently elevated FVIII is less likely to be found in UE-DVT patients than in those with LE-DVT and is the only thrombophilia that is differentially expressed after controlling for established VTE risk factors [OR 0.46, (95% CI 0.25-0.83)]. Although less prevalent than in LE-DVT patients, thrombophilia is a common finding in patients with UE-DVT, especially in those with thrombosis that is unrelated to venous catheters.     

Absolute annual incidences of first events of venous thromboembolism and arterial vascular events in individuals with elevated FVIII:c. A prospective family cohort study

Elevated levels of factor VIII:c (elevated FVIII:c) are associated with an increased risk for venous thromboembolism (VTE) and arterial vascular events, and are at least in part determined genetically. We prospectively followed 192 asymptomatic individuals with elevated FVIII:c (>150%) and 340 with normal levels for an average duration of 31 months (range 7 to 56 months) to investigate the risk of VTE and arterial vascular events. Participants were first degree relatives of consecutive patients with elevated FVIII:c and VTE or arterial vascular events before the age of 50 years. The incidences of VTE were 1.25% (0.46-2.73) per year in the subjects with elevated FVIII:c, versus 0.23% (0.03-0.82) in those with normal levels (OR 5.5 [1.1-27.3]). The annual incidences of arterial vascular events were 1.04% (0.34-2.42) and 0.23% (0.03-0.82) in relatives with and without elevated levels of FVIII:c, respectively (OR: 4.5 [0.9-23.5]). After adjustment for age, smoking, known diabetes mellitus, hyperlipidemia, and hypertension, the odds ratio for any event was 3.7 (1.1-13.1). In conclusion, asymptomatic individuals with elevated FVIII:c levels and a positive family history of VTE or arterial vascular events before the age of 50 appear to have a high annual incidence of first VTE and arterial vascular events. Elevated FVIII:c may be a common risk factor for both clinical entities.     

Comparison of three activated protein C resistance tests in the risk assessment of venous thrombosis in non-carriers of the factor V Leiden mutation

Activated protein C resistance (APCR), measured using the original assay described by Dahlb?ck, is a risk factor for venous thrombosis independent of the factor V Leiden (FVL) mutation. This assay is based on the activated partial thromboplastin time (APTT) after plasma exposure to activated protein C (APC). As this assay was sensitive to numerous interferences, new assays have been developed for FVL screening. The objectives of the study were to investigate the association of second generation assays for APCR with venous thrombosis in FVL non-carriers. One hundred ninety-seven subjects with a history of venous thrombosis and 211 controls were explored using 3 APCR assays, the original APTT-based assay (test A), an APTT-based assay with factor V depleted plasma pre-dilution (test B) and a direct factor X activation-based assay with the same pre-dilution (test C). We found that subjects with results in the lowest quartile of the APTT-based assays are at increased risk, compared to those in the highest quartile (test A Odds Ratio = 6.39; 95% CI 3.23-12.63; test B OR = 2.72; 95% CI 1.50-4.94). There was no significant risk increase associated with test C results. After adjusting for FVIII levels, the ORs of tests A and B were similar (test A OR = 3.22; 95% CI 1.47-7.08; test B OR = 3.10; 95% CI 1.54-6.21). In conclusion, APTT-based assays, but not direct factor X activation-based assays, effectively detect the risk for venous thrombosis independent of FVL. Pre-dilution in factor V depleted plasma is an effective way to directly assess the risk independent of FVIII levels.     

Elevated factor VIII in hereditary haemorrhagic telangiectasia (HHT): association with venous thromboembolism

Hereditary haemorrhagic telangiectasia (HHT) causes chronic nasal and gastrointestinal haemorrhage. Prothrombotic agents are commonly used for severe haemorrhage. Thrombotic risks have not been defined. In order to identify prothrombotic variables in HHT patients, and assess their potential functional significance, a pilot ELISA-based study comparing plasma proteins in healthy individuals with HHT to age/sex-matched non-HHT controls was validated in a full study of 309 consecutive HHT-affected individuals. In the pilot study, factor VIII (FVIII) and von Willebrand factor antigen concentrations were elevated in the HHT group compared to non-HHT controls (p<0.0013, Mann-Whitney). Service laboratory measurements confirmed high FVIII:Ag in 125 HHT-affected individuals with no recent ill-health, intervention or venous thromboemboli. FVIII:Ag levels increased with age. Logistic regression also suggested an age-independent association with HHT-associated pulmonary arteriovenous malformations (AVMs). No association was demonstrated between FVIII:Ag and acute phase response, disseminated intravascular coagulation, ABO group, pulmonary artery pressure, or markers of HHT haemorrhage. Elevated FVIII:Ag were associated with shortened activated partial thromboplastin times (APTTs), and VTE:VTE affected 20/309 (6.5%) HHT-affected individuals, at median age 61(36-71) years. Four VTE occurred in factorV Leiden heterozygotes in the months following PAVM-associated brain abscess. The strongest association with VTE was with log-transformed FVIII:Ag measured 10-132 months from VTE (odds ratio 2.41, 95% confidence intervals 1.254, 4.612, p=0.008). Age made no additional contribution to VTE risk once adjusted for FVIII:Ag. In conclusion, HHT-related elevation of FVIII:Ag levels may influence thrombotic risk in HHT. Individualised risk-benefit considerations may be helpful in HHT management.     

Basal high-sensitivity-C-reactive protein levels in patients with spontaneous venous thromboembolism

The role of C-reactive protein (CRP) in venous thromboembolism (VTE) is still under discussion because of controversial results in the literature. Conflicting data may have partly been due to bias by exogenous factors altering CRP levels. We investigated CRP concentrations in patients with spontaneous VTE applying a study design that allowed the measurement of basal high sensitivity (hs)-CRP levels. Patients with a history of deep vein thrombosis (DVT, n=117) and pulmonary embolism (PE, n=97) were compared to healthy individuals (n=104). Hs-CRP levels (mg/dl) were significantly higher in patients (n=214, median/interquartile range: 0.171/0.082-0.366) than in controls (0.099/0.053-0.245, p=0.001). The unadjusted odds ratio (OR) for VTE per 1 mg/dl increase of CRP was 2.8 [95% confidence interval (CI): 1.1-6.8, p=0.03]. This association remained significant after adjustment for factor V Leiden, prothrombin G20210A and factor VIII activity above 230% (OR = 2.9, 95% CI [1.1-7.5]), but became remarkably attenuated and lost its statistical significance after adjustment for BMI alone (OR = 1.7 [0.7-4.0]). CRP was also not independently associated with VTE in subgroups of patients (those with DVT without symptomatic PE, those with PE and patients without established risk factor) in multiple regression analysis. In summary, we observed significantly higher basal hs-CRP levels in patients with spontaneous VTE compared to healthy controls. This association was independent of hereditary and laboratory risk factors for VTE, but lost its significance after adjustment for BMI. Increased basal CRP levels do not appear to represent an independent risk factor for VTE.     

Maternal smoking, obesity, and risk of venous thromboembolism during pregnancy and the puerperium: a population-based nested case-control study

BACKGROUND: Smoking and obesity are associated with adverse pregnancy outcomes. The aim of the present study was to examine the association between smoking, obesity (BMI>30), and risk for venous thromboembolism (VTE) during pregnancy and the puerperium. MATERIALS AND METHODS: In a population-based case-control study nested within a Danish cohort of 71,729 women, we identified 129 cases with VTE in pregnancy or the puerperium, and 258 pregnant non-VTE controls. We obtained data from medical records regarding current smoking status, BMI, and other covariates, and computed the odds ratios (OR) for VTE as a measure of relative risk. RESULTS: Smoking and obesity were associated with increased risk of VTE during pregnancy and the puerperium (adjusted OR 2.7 (95% CI: 1.5, 4.9) and 5.3 (95% CI: 2.1, 13.5), respectively). Obesity appeared to be associated with a higher risk of pulmonary embolism (adjusted OR: 14.9 (95% CI: 3.0, 74.8) than of deep venous thrombosis (adjusted OR: 4.4, 95% CI: 1.6, 11.9). CONCLUSION: Smoking and obesity are risk factors for VTE in pregnancy and the puerperium.     

Evaluation of ProC Global assay in women with a history of venous thromboembolism on hormonal therapy

The risk of thrombosis in women increases significantly during treatment with hormonal therapy (HT). The aim of this study was to evaluate ProC Global assay in women with a history of venous thromboembolism (VTE) while using HT. Protein C activation time normalized ratio (PCAT-NR) levels were significantly lower in 32 women with a history of VTE while using HT (0.72 +/- 0.1) compared with 56 healthy controls without HT, matched by age at blood sampling (0.99 +/- 0.2) and 40 healthy controls with HT, matched by age and HT at VTE event (0.94 +/- 0.2) (P < 0.001 for both). PCAT-NR lower than the cut-off level of 0.8 was found in 23/32 (72%) patients compared with 5/56 (9%) age-matched controls (OR = 26, 95%CI: 7-106, P < 0.001) and 9/40 (22.5%) of HT-matched controls (OR = 9, 95%CI: 2.7-30, P < 0.001). Any thrombophilic risk factor was found in 20/32 (62.5%) of patients compared with 12/56 (21.4%) of agematched controls (OR = 6, 95%CI: 2.1-10, P < 0.001) and 12/40 (30%) of HT-matched controls (OR = 4, 95%CI: 1.3-11.8, P = 0.006). Out of the variables that are risk factors of VTE as age, HT or thrombophilic risk factor, ProC Global assay was found in the multivariate analysis - logistic regression, as the parameter that was the most associated with patient group [Exp(B) = 15.8, 95% CI: 4.2-59.0, P < 0.001]. In conclusion, abnormal PCAT-NR is associated with VTE in women using HT. ProC Global assay may potentially serve as a diagnostic tool for evaluating the risk of VTE in women prior to administration of HT.     

Persistent high factor VIII activity leading to increased thrombin generation - a prospective cohort study

Introduction

A persistently elevated level of factor VIII (FVIII) is an independent risk factor for venous thromboembolism (VTE). Although the pathophysiology of VTE is unclear, the involvement of thrombin generation (TG) has been postulated. Consequently this study was designed to (i) investigate the relationships between FVIII, Thrombin generation test (TGT) parameters and D-dimer in VTE patients, (ii) determine whether elevated levels of FVIII and increased TG in these patients are transient or sustained.

Patients and Methods

After an initial period of anticoagulation had been completed 91 VTE patients and 52 healthy controls were recruited. FVIII levels were determined by one-stage clotting (FVIII:C) and chromogenic (FVIII:Ch) assays. The potential to generate thrombin was measured using the Calibrated Automated Thrombogram (CAT) and D-Dimer was by immuno-turbidometric assay.

Results

Patients' FVIII:C levels and FVIII:Ch, exhibited good agreement (rs = 0.94; p < 0.0001), although FVIII:C exhibited a mean bias of -6%. FVIII:Ch show a significant correlation with TGT Peak Thrombin (rs = 0.30; p = 0.004) and Peak Thrombin was found to be significantly higher (p = 0.04) in patients with FVIII > 200 iu/dL. Furthermore elevated levels of FVIII and increased thrombin generation parameters appeared to be consistent over time.

Conclusion

Our data suggests that high FVIII leading to increased TG confers a significant risk of recurrent VTE and therefore we speculate that these patients may benefit from prolonged anticoagulation therapy.     

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 risk of recurrent venous thromboembolism in carriers and non-carriers of the G1691A allele in the coagulation factor V gene and the G20210A allele in the prothrombin gene. DURAC Trial Study Group. Duration of Anticoagulation.

The results concerning the risk of recurrent venous thromboembolism (VTE) in carriers of the G1691A mutation in the coagulation factor V gene are not consistent and this risk in carriers of the G20210A polymorphism in the prothrombin gene has hitherto not been reported. We followed 534 patients for 48 months after their first episode of objectively documented VTE. The prevalence of the G1691A allele in 467 (87.5%) of the patients and in 207 controls was 25.3% and 8.2%, respectively, in heterozygote form and 2.4% and 0.5%, respectively, in homozygote form. The adjusted odds ratio (OR) for the first VTE was 4.4 (95% CI 2.6-7.8). The risk of recurrent VTE in heterozygotes was not statistically different from non-carriers (17.8% vs 17.6%), with 85% power to detect a hazard ratio of 2.35. Homozygotes had a significantly increased risk (p = 0.036) of recurrent VTE. The prevalence of the G20210A allele in 456 patients and 207 controls was 6.1% and 1.4%, respectively. The adjusted OR was 4.6 (95% CI 1.6-19.3) for the first VTE in 28 carriers of this polymorphism. The risk of recurrent VTE for these was not statistically different from non-carriers with an OR of 0.9 (95% CI 0.2-2.9).