Liver Cirrhosis Patients Homozygous for MTHFR C677T Develop Portal Vein Thrombosis 8 Years Earlier Than Wild Type.

BACKGROUND AND AIM: Age at portal vein thrombosis (PVT) in liver cirrhosis (LC) carriers of the methylene tetrahydrofolate reductase (MTHFR) rs1801133 (C → T667 transition) polymorphism has never been addressed; we compared age at PVT in LC patients genotyped for the MTHFR and explored the interrelated clinical and laboratory factors predicting age at PVT. APPROACH AND RESULTS: Retrospective cross-sectional cohort study. PVT participants: MTHFR CC n = 36, MTHFR CT n = 53, MTHFR TT n = 19; age, sex, age at PVT, Child-Pugh score, rs1799963 PT polymorphisms (G → A 20,210 transition), plasma HC and natural anticoagulants available for all participants. Age at PVT was lower in MTHFR TT than CT and CC (56 ± 13 vs. 57 ± 13 vs. 64 ± 9 years, p = 0.001); median (IQR) plasma HC was higher in MTHFR TT than in the other groups [(17 (9.4, 23.3) vs 13 (8,14.7) vs 11 (8.9, 12.7) µmol/l, p = 0.03)]. MTHFR TT, male gender and protein C predicted age at PVT (p = 0.02, p = 0.04 and p = 0.08); MTHFR TT and Child-Pugh score predicted plasma HC (p = 0.005 and p = 0.01) as well as low plasma protein C (p < 0.0001 and p = 0.0002). Plasma HC inversely related to protein C in the MTHFR TT group (p < 0.0001). Compound MTHFR TT with PT GA had lower age at PVT compared to MTHFR TT alone (49 ± 18 vs 58 ± 12 years). CONCLUSIONS: MTHFR TT anticipates PVT associated with LC by an average of 8 years; MTHFR TT associates with severity of liver disease and to high plasma HC; the latter may contribute to the prematurity of PVT by interfering with the anticoagulant activity of protein C.

Juvenile patients with the homozygous MTHFR C677T genotype develop ischemic stroke 5 years earlier than wild type.

To compare age at 1st ischaemic stroke (IS) in a cohort of juvenile (< 46 years of age) IS patients evaluated for the rs1801133 polymorphism (C → T677) of the methylene tetrahydrofolate reductase (MTHFR) gene; to identify predictors of age at IS and of type of cerebral vessel involvement, small vessel disease (SVD) vs large vessel disease (LVD) responsible for the IS; to evaluate possible associations between other clinical and laboratory variables. Retrospective cohort study on 82 MTHFR TT, 54 MTHFR TC and 34 MTHFR CC participants; data regarding age, sex, age at IS, history of dyslipidaemia, hypertension, smoking, migraine and homocysteine (HC) as well as neuroimaging were collected. Age at IS was lower in MTHFR TT than MTHFR TC and CC (35 ± 4 vs 38 ± 0 vs 40 ± 3 years, respectively, p = 0.002); plasma HC (median, interquartile range) was higher in MTHFR TT than in the other groups [16.7 (11.8, 28.6) vs 11.4 (8.2, 16.1) vs 9.8 (7.9, 1.3) respectively, p < 0.0001)] and was higher in SVD than LVD [17.4 (12.4, 32.5) vs  11.4 (8.8, 16.4) p < 0.0001]. MTHFR TT independently predicted age at IS (p = 0.0008) alongside smoking both as a categorical (p = 0.003) or continuous variable (p = 0.02), whereas HC independently predicted SVD as categorical (p = 0.01) and continuous variable (p < 0.0001). Smoking positively predicted plasma HC (p = 0.005) and negatively the activated partial thromboplastin ratio (aPTTr) (p = 0.02). Juvenile IS carriers of the MTHFR TT genotype develop their 1st occlusion on average 5 years earlier compared to the CC genotype; smoking contributes to this prematurity adversely affecting plasma HC and coagulation whereas plasma HC predicts IS secondary to SVD. Public health campaigns against smoking should highlight the prematurity of IS in the juvenile population.

Validity of Coagulation Activation Markers in Antiphospholipid Syndrome: A Systematic Review and Meta-analysis with a Short Data Report.

Prothrombin fragment F1 + 2 (F1 + 2) and thrombin-antithrombin (TAT) have been assessed in antiphospholipid syndrome (APS) but without evaluating a direct relationship with antiphospholipid (aPL) antibody titers. This article aims to investigate a direct relationship between aPL and F1 + 2 and perform a systematic review and meta-analysis of F1 + 2 and TAT in APS. Systematic search was performed using EMBASE and PubMed databases from January 1982 to December 2018 and random effects meta-analyses for continuous outcomes. This is a cross-sectional case-control study; immunoglobulin G/immunoglobulin M (IgG/IgM) anticardiolipin (aCL) anti-ß2-glycoprotein-I, antiprothrombin (aPT) antibodies, F1 + 2, and lupus anticoagulants (LA) were measured in 25 thrombotic primary APS (PAPS), 9 nonthrombotic carriers of aPL, and 18 controls. The significant effect size (ES) for F1 + 2 between aPL +ve and aPL -ve systemic lupus erythematosus (SLE) and between aPL +ve SLE and control displayed high heterogeneity. The significant ES for F1 + 2 between aPL -ve SLE and controls displayed no heterogeneity. The ES for TAT between aPL +ve and aPL -ve SLE patients and between aPL -ve SLE and controls was low, without heterogeneity. Mean F1 + 2 was greater in PAPS (p < 0.0001), inversely correlated with IgG aCL, IgM aPT, and LA (p = 0.001, 0.03, and 0.01, respectively), though only IgG aCL negatively predicted F1 + 2 (p = 0.01). IgG aCL inversely predicts F1 + 2. IgG aCL positivity introduces heterogeneity in the F1 + 2 ES, whereas the lack of heterogeneity in the ES for TAT may indicate poor TAT formation in aPL +ve group. Thus, F1 + 2 measurements may be unfounded as already demonstrated for TAT in the 1990s.

Homozygous MTHFR C667T carriers ≤45 years old develop central retinal vein occlusion five years earlier than wild type.

PURPOSE: To assess age at 1st central retinal vein occlusion (CRVO) in carriers ≤ 45 years old of the methylenetetrahydrofolate reductase (MTHFR) C667T genotype compared to heterozygous and wild type, and to identify predictors of age at CRVO. METHODS: Retrospective cohort study consisting of 18 MTHFR TT, 23 MTHFR TC and 28 MTHFR CC participants; information regarding age, sex, age at CRVO, history of dyslipidaemia, hypertension, smoking and plasma HC measured by immunoassay were collected. RESULTS: Age at CRVO was lower in MTHFR TT than MTHFR TC and CC (32 ± 6 vs 38 ± 5 vs 37 ± 6 years, respectively, p = 0.005); plasma HC was higher in MTHFR TT than in the other genotypes [14.4 (10.8, 19.6) vs 10.4 ((8.6,12.5) vs 8.5 ((7.5,9.8) µmol/l, p = 0.0002). Smoking (cigarettes/day) independently predicted age at CRVO (p = 0.039) and plasma HC (p = 0.005); smoking status (yes/no) predicted ischemic CRVO (p = 0.01) that was more common in the MTHFR TT group (p = 0.006). CONCLUSIONS: Carriers of the MTHFR TT genotype ≤ 45 years old develop their 1st CRVO on average 5 years earlier than the MTHFR CC genotype; smoking contributes to the prematurity and severity of CRVO in MTHFR TT carriers.

Homozygous MTHFR C677T carriers develop idiopathic portal vein thrombosis 20 years earlier than wild type.

The aim of this study was to evaluate the impact of methylene tetrahydrofolate reductase (MTHFR) rs1801133 (C→T667 transition) on age at first idiopathic portal vein thrombosis (PVT) and to identify clinical and/or laboratory variables influencing age at first PVT, including plasma homocysteine and the prothrombin rs1799963 PT (G→A transition at position 20210) (PT) mutation. A retrospective cross-sectional cohort, including 15 MTHFR TT, 32 MTHFR TC and 22 MTHFR CC idiopathic PVT participants contributing demographics, age at PVT, plasma concentrations of homocysteine and of natural anticoagulants. MTHFR TT carriers presented with a lower age at PVT than heterozygous or wild-type genotypes (31 ±â€Š8 vs. 48 ±â€Š15 vs. 52 ±â€Š13 years, P  = 0.001) and were more likely to have a plasma HC concentration above the cut-off (73.3 vs. 32 vs. 50%, P  = 0.04). MTHFR TT and protein C predicted age at PVT ( P  < 0.0001 and P  = 0.06); MTHFR TT predicted plasma homocysteine ( P  = 0.05). In the MTHFR TT group, plasma homocysteine inversely related to protein C ( P  = 0.03). Plasma homocysteine predicted the extent of PVT ( P  = 0.03). Compound MTHFR TT + PT GA did not lower age at first PVT compared to MTHFR TT alone (35 ±â€Š9 vs. 30 ±â€Š8 years). MTHFR TT is associated with a 20-year earlier PVT presentation than heterozygous and wild-type MTHFR genotypes. The inverse relation between plasma homocysteine and protein C contributes to the prematurity of PVT in the MTHFR TT group, whereas plasma homocysteine contributes to the extent of PVT. The recent exclusion of MTHFR genotyping from the thrombophilia screen needs revisiting in this setting.

Earlier onset of peripheral arterial thrombosis in homozygous MTHFR C677T carriers than in other MTHFR genotypes: a cohort study.

To investigate whether age at first presentation of pure peripheral arterial thrombosis (PAT) in lower and upper limbs and in the splanchnic circulation occurs earlier in carriers of the methylenetetrahydrofolate reductase (MTHFR) T677T genotype compared to the heterozygous and wild type and to identify predictors of a possible earlier onset. Retrospective cohort study on 27 MTHFR TT, 29 MTHFR TC and 29 MTHFR CC participants; data regarding age, sex, age at PAT, clinical history (dyslipidaemia, hypertension, smoking, obesity) and homocysteine (HC) measured by immunoassay were collected. Age at PAT was lower in MTHFR TT than MTHFR TC and CC (43 ± 9 vs 47 ± 9 vs 51 ± 4 years, respectively, p = 0.02); plasma HC was higher in MTHFR TT than in the other groups (25 ± 19 vs 12.7 ± 6.7 vs 11.3 ± 3.3 µmol/l, respectively, p < 0.001) while the activated partial thromboplastin ratio (aPTTr) was lower in MTHFR TT than in other genotypes (0.90 ± 0.10 vs 0.97 ± 0.12 vs 0.97 ± 0.08 µmol/L p < 0.001). Among categorical variables, MTHFR TT and dyslipidaemia independently predicted age at AT (p = 0.01 & p = 0.03, respectively) whereas among the continuous variables HC independently predicted age at PAT (p = 0.02) as well as the aPTTr (p = 0.001); smoking predicted lower limb PAT (p = 0.005). MTHFR TT carriers develop their first PAT an average of 4 and 8 years earlier than MTHF CT and CC genotypes; MTHFR TT, dyslipidaemia and plasma HC contribute to the prematurity of the PAT while the interplay between elevated HC and smoking may affect type of arterial district occlusion.

Composition and biodiversity of soil and root-associated microbiome in Vitis vinifera cultivar Lambrusco distinguish the microbial terroir of the Lambrusco DOC protected designation of origin area on a local scale.

Introduction: Wines produced from the same grape cultivars but in different locations possess distinctive qualities leading to different consumer's appreciation, preferences, and thus purchase choices. Here, we explore the possible importance of microbiomes at the soil-plant interface as a determinant of the terroir properties in grapevine production, which confer specific growth performances and wine chemo-sensory properties at the local scale. Methods: In particular, we investigated the variation in microbial communities associated with the roots of Vitis vinifera cultivar Lambrusco, as well as with surrounding bulk soils, in different vineyards across the "Consorzio Tutela Lambrusco DOC" protected designation of origin area (PDO, Emilia Romagna, Italy), considering viticultural sites located both inside and outside the consortium in two different seasons (June and November 2021). Results: According to our findings, rhizospheric and soil microbiomes show significant structural differences in relation to the sampling site, regardless of seasonality, while endophytic microbiomes seem to be completely unaffected by such variables. Furthermore, a deeper insight into the microbial terroir of PDO areas highlighted the presence of some rhizospheric microorganisms enriched inside the consortium and characterizing the PDO regardless of both sampling season and farming strategy. These include Bacillus, Paenibacillus, and Azospirillum, which are all well-known plant growth-promoting bacteria. Discussion: Taken together, our results suggest a connection between soil and root microbiomes of V. vinifera cultivar Lambrusco and the local designation of origin, emphasizing the potential role of PDO-enriched plant growth-promoting bacteria in vine growing and final quality of the Lambrusco DOC wine.

Intensity of immune/clotting assays relate to multiple antiphospholipid antibody positivity in thrombotic primary antiphospholipid syndrome.

The dual positivity (DP) and triple positivity (TP) concepts bypass the poor comparability of immune/clotting assay for the laboratory classification of antiphospholipid syndrome (APS). To evaluate intensity of immune/clotting assays and DP/TP through different clinical severity groups (CSG) as follows: (1) non-thrombotic asymptomatic carriers of aPL (N-THR), thrombotic primary APS (THR), deceased (D) for recurrent and fatal thrombosis. Activated partial thromboplastin time ratio (aPTTr), dilute Russell viper venom time ratio (DRVVTr), IgG/IgM anticardiolipin (aCL) and anti ß-2-glycoprotein-I (aß2GPI). Participants: 33 N-THR, 64 THR and 11 D. The frequency of DP and TP (DRVVTr or aPTTr partnered with respective IgG aCL or aß2GPI) increased across CSG (p = 0.006 and p = 0.003); mean DRVVTr and IgG aCL/aß2GPI were always greater in TP versus non-TP within each CSG and progressively increased across the CSG. The intensity of individual lupus anticoagulants partnered with their corresponding IgG aPL related to the frequency of multiple positivity throughout CSG suggesting that of intensity of immune/clotting assays and multiple positivity are the different faces of the same diagnostic coin in our thrombotic PAPS cohort.

Homozygous methylentetrahydrofolate reductase C667T genotype anticipates age at venous thromboembolism by one decade.

The aim of the study was to compare age at first venous thromboembolism (VTE), plasma homocysteine and activated partial thromboplastin time ratio (aPTTr) amongst unprovoked VTE patients with the methylentetrahydrofolate reductase (MTHFR) C667T genotypes, and to identify predictors of age at first VTE, of plasma homocysteine and of the aPTTr; to evaluate whether heterozygous or homozygous prothrombin (PT) G20210A mutation lowered the age at first VTE when associated with MTHFR TT. Retrospective cohort study on 259 MTHFR TT, 76 MTHFR TC and 64 MTHFR CC participants with unprovoked VTE; each participant contributed age, sex, age at VTE, history of dyslipidaemia, hypertension, smoking, homocysteine (measured by enzyme immunoassay) and aPTTr (measured by standard coagulation assay). Age at first VTE was lower in MTHFR TT than MTHFR TC and CC (41 ±â€Š14 vs. 50 ±â€Š16 vs. 51 ±â€Š12 years, respectively, P < 0.0001); plasma homocysteine was higher in MTHFR TT than in the other groups (22 ±â€Š21 vs. 12 ±â€Š11.6 vs. 10 ±â€Š3.3 µmol/l, respectively, P = 0.0005) whilst aPTTr was not different. MTHFR TT independently predicted age at first VTE (P = 0.001), plasma homocysteine (P < 0.0001) alongside sex (P = 0.0007), age and smoking (P = 0.03 for both). Compound MTHFR TT with PT GA or AA had no lowering effect on age at first VTE compared with MTHFR TT alone (41 ±â€Š13 vs. 41 ±â€Š14 years). Plasma homocysteine inversely related to aPTTr in the MTHFR TT group (P = 0.003). MTHFR TT anticipates age at first VTE by an average of 10 years compared with MTHFR TC and CC genotypes.

Occurrence of the JAK2 V617F mutation in the Budd-Chiari syndrome.

Myeloproliferative diseases represent a major risk factor for Budd-Chiari syndrome. In 32 patients with Budd-Chiari syndrome, the JAK2 V617F mutation was detected, in heterozygous state, in 11 individuals (34.4%; 95% confidence interval: 18.6-53.2). Eight patients with (72.7%; 95% confidence interval: 39.0-94.0) and six without (28.6%; 95% confidence interval: 11.3-52.2) the JAK2 V617F mutation had a diagnosis of myeloproliferative diseases before or at the occurrence of the venous thrombotic event. In three patients carrying the JAK2 V617F mutation, a myeloproliferative disease was not detected. Determination of the JAK2 V617F mutation may be useful to recognize patients with Budd-Chiari syndrome with or at risk for the subsequent development of overt myeloproliferative diseases.

Gain-of-function gene mutations and venous thromboembolism: distinct roles in different clinical settings.

OBJECTIVE: To calculate the prevalence of common gain of function gene mutations in patients with different clinical manifestations of venous thromboembolism. DESIGN AND SETTING: Case-control study in two hospitals in Italy. PARTICIPANTS: 387 patients with venous thromboembolism and 286 controls. MAIN MEASURES: Factor V (FV) Leiden, factor II (FII) A20210 and JAK2 V617F mutations. RESULTS: Among patients with deep vein thrombosis in one leg, 23 (20.9%) carried FV Leiden and FII A20210 mutations. Similar figures were observed in patients with cerebral vein thrombosis (CVT; n = 9; 20.0%) and in patients presenting with splanchnic vein thrombosis (SVT; n = 26; 18.7%). A lower prevalence was obtained in patients with retinal vein thrombosis (n = 11; 11.8%). The JAK2 F617 mutant allele was found in 27 (21.1%) patients with SVT, but in none of the patients presenting with a thrombotic event from different districts. 13 of the 27 JAK2 V617F-positive subjects with SVT were previously known to have a myeloproliferative disease (MPD). Three other patients had a diagnosis of MPD after the occurrence of the thrombotic event. CONCLUSION: Carriership of FV Leiden or FII A20210 mutations identifies an at-risk condition for venous thrombosis in the lower extremities, SVT or CVT. In patients with SVT, screening for the JAK2 V617F mutation may be useful in recognising patients who should be carefully observed for the subsequent development of overt MPD. Thus, genetic tests may play a different role, various clinical manifestations of venous thromboembolism being associated with distinct risk profiles.

Predictive Value of Oxidized Low-Density Lipoprotein/ß2-Glycoprotein-I Complexes (oxLDL/ß2GPI) in Nonautoimmune Atherothrombosis.

INTRODUCTION: Lipid oxidation is a definite feature of atherosclerosis, and oxidized low-density lipoprotein (oxLDL) is not only highly immunogenic but toxic to several cell types. Beta-2-glycoprotein-I (ß2GPI) dampens oxLDL toxicity by forming binary oxLDL/ß2GPI complexes. We evaluated whether circulating oxLDL/ß2GPI complexes are associated to atherosclerosis-related events (ARE) and to venous thromboembolism (VTE). METHODS: In a cross-sectional case-control study, cases were (a) 57 consecutive patients (male/female [M/F] 33/24, mean age 57 [10] years) attending a thrombosis unit for ARE (myocardial infarction [MI] n = 20, peripheral vascular disease n = 7, and ischemic strokes n = 30); (b) 52 consecutive patients (M/F 22/30, mean age 55 [17] years) attending the same unit for unprovoked (VTE); (c) normal controls comprised 90 participants (M/F 35/55, mean age 41 [15] years); and (d) oxLDL/ß2GPI complexes were measured by immunoassay and resulting levels divided into quartiles. RESULTS: The odds ratio (OR) of ARE was greater in the fourth and second quartiles than in the first quartile (8.5 and 6.0, respectively); the OR of developing MI was greatest in the fourth quartile (17.8). By multivariable analysis with age, sex, smoking, lipid status, statin, and ARE phenotypes as independent variables and oxLDL/ß2GPI as the dependent variable, only MI predicted oxLDL/ß2GPI ( P < .0001). CONCLUSIONS: OxLDL/ß2GPI may be regarded as a marker of ARE, in particular of MI.

Subclinical atherosclerosis in primary antiphospholipid syndrome.

To test the atherosclerosis hypothesis in primary antiphospholipid syndrome (PAPS) we measured intima media thickness (IMT) of carotid arteries and other cardiovascular risk factors in 44 patients with PAPS (mean age 35 +/- 12 years), in 25 patients with inherited thrombophilia (mean age 40 +/- 10 years), and in 34 normal controls (mean age 38 +/- 11 years). The frequency of smoking, hypertension, and dyslipidemia was similar across groups. IMT was almost similar across groups at age groups below 40 years but IMT was greater in PAPS than controls at the common carotid (P = 0.01), at the bifurcation (P = 0.003), and at the internal carotid (P = 0.005) in the age group over 40 years. Atherosclerosis is a possibility in PAPS patients in their fourth decade of life or older.

Increased plasma prothrombin concentration in cirrhotic patients with portal vein thrombosis and prothrombin G20210A mutation.

It was the aim of the present study to investigate factor II levels in liver cirrhosis (LC) patients with portal vein thrombosis (PVT) carrying the heterozygous G20210A prothrombin (PT) mutation. Plasma concentrations of factor II, VII, X, V, protein C (PC) total protein S (tPS) antithrombin (AT) and D-dimers (DD) were measured in 13 LC patients with PVT heterozygous for PT G20210A, in 13 LC patients with PVT without PT G20210A and in 13 LC controls matched by age, sex and Child-Pugh score. Crude factor II and factor II/DD ratio were highest in LC patients with PVT heterozygous for PT G20210A (p = 0.03 and p = 0.02 respectively). The factor II/PC ratio, expression of a procoagulant/anticoagulant imbalance was highest in the same group (p = 0.0008). Plasma factor II levels are elevated in LC patients heterozygous for PT G20210A and may favour PVT.

Hepatic vein thrombosis leading to fulminant hepatic failure in a case of acute non-promyelocytic myelogenous leukemia.

Budd-Chiari syndrome is a rare disease due to occlusion of the hepatic veins often presenting with acute liver failure. Common causes of Budd-Chiari syndrome are chronic myeloproliferative disorders, while acute leukemia has been associated with hepatic vein thrombosis in only two cases in the literature to date. We report a case of Budd-Chiari syndrome complicating a non-promyelocytic acute myelogenous leukemia leading to fulminant hepatic failure.

Survival in primary antiphospholipid syndrome. A single-centre cohort study.

The vascular mortality of antiphospholipid syndrome (APS) ranges from 1.4 % to 5.5 %, but its predictors are poorly known. It was the study objective to evaluate the impact of baseline lupus anticoagulant assays, IgG anticardiolipin (aCL), plasma fibrinogen (FNG) and von Willebrand factor (VWF), platelets (PLT) and of genetic polymorphisms of methylenetetrahydrofolate reductase C677T, of prothrombin G20210A and of paraoxonase-1 Q192R on survival in primary APS (PAPS). Cohort study on 77 thrombotic PAPS and 33 asymptomatic carriers of aPL (PCaPL) seen from 1989 to 2015 and persistently positive for aPL as per annual review. At baseline all participants were tested twice for the ratios of kaolin clotting time (KCTr), activated partial thromboplastin time (aPTTr), dilute Russell viper venom time (DRVVTr), IgG aCL, FNG, VWF and once for PLT. All thrombotic PAPS were on warfarin with regular INR monitoring. During follow-up 11 PAPS deceased (D-PAPS) of recurrent thrombosis mostly arterial, despite adequate anticoagulation yielding an overall vascular mortality of 10 %. D-PAPS had the strongest baseline aPTTr and DRVVTr and the highest mean baseline IgG aCL, FNG, VWF and PLT. Cox proportional hazards model identified baseline DRVVTr and FNG as main predictors of mortality with adjusted hazard ratios of 5.75 (95 % confidence interval [CI]: 1.5, 22.4) and of 1.03 (95 %CI: 1.01, 1.04), respectively. In conclusion, plasma DRVVTr and FNG are strongly associated with the risk of vascular death in PAPS; while FNG lowering agents exist further research should be directed at therapeutic strategies able to dampen aPL production.

Bleeding and re-thrombosis in primary antiphospholipid syndrome on oral anticoagulation: an 8-year longitudinal comparison with mitral valve replacement and inherited thrombophilia.

The aim of this study was to compare bleeding and re-thrombosis in primary antiphospholipid syndrome (PAPS), mitral valve replacement (MVR) and inherited thrombophilia (IT) at different oral anticoagulation intensities. It entailed a prospective 8-year follow-up on 67 patients with PAPS, 89 with IT and 24 with MVR. Anticardiolipin (aCL) antibodies detected by Elisa and lupus anticoagulant by clotting assays. At INR 2-3 minor bleeding rate was higher in MVR (33.3) than PAPS (10.9) and IT (4.2)(p<0.0001). At INR 3-4 minor bleeding rate was higher in PAPS (142) than IT (33.3) and MVR (5.8)(p<0.0001). At either INR major bleeding rate were not significantly different across the three groups, but in PAPS major and minor bleeding rates were superior at INR 3-4 than INR 2-3 (p=0.02 and p<0.0001). Re-thrombosis rate was higher in PAPS than IT at INR 2-3 (4.0 vs 0.35) (p=0.01) and at INR 3-4 (10.5 vs. nil). The hazard ratio for re-thrombosis between PAPS and IT was 13 (95% IC 1.6-102.2, p=0.015). By regression analysis, baseline IgG aCL titre (>80 GPL) p=0.001) and male sex (p=0.03) independently predicted re-thrombosis. In conclusion, in PAPS, high intensity oral anticoagulation was not superior to conventional intensity in preventing re-thrombosis but was offset by greater bleeding rates. Male sex and elevated baseline IgG aCL predicted rethrombosis in PAPS that is 13-fold more re-thrombogenic than IT.

Prolonged Activated Partial Thromboplastin Time: Difficulties in Discriminating Coexistent Factor VIII Inhibitor and Lupus Anticoagulant.

To review the diagnostic difficulties of a prolonged activated partial thromboplastin time (aPTT) when 2 inhibitors with opposite clinical presentations coexist, we searched MEDLINE from January 1970 to November 2013 using acquired, factor VIII (FVIII), factor IX, hemophilia A and B, inhibitor, lupus anticoagulant (LA), antiphospholipid, anticardiolipin, anti-ß2-glycoprotein I, antibodies, syndrome, bleeding, and thrombosis. We identified 13 articles for a total of 15 cases of possible coexistence of FVIII inhibitor and LA. The presenting clinical manifestation was thrombosis in 6 cases and bleeding in 9 cases. Activated partial thromboplastin time was the presenting laboratory abnormality in all cases, and first-line investigations suggested the coexistence of LA and acquired FVIII inhibitor. None of the articles addressed the diagnostic accuracy of the screening tests by performing "second line" assays. We reviewed the diagnostic pitfalls of the cases under study and provide some guidance for alternative tests when facing a prolonged aPTT that may have a double meaning.

Rescue of activated protein C-resistance phenotype by cis-acting factor V Gly2032Asp mutation.

A 60-year-old Italian woman presenting with factor VLeiden mutation but a normal activated protein C (APC) resistance, low functional and antigenic factor (FV) plasma levels, was found to have a novel heterozygous Gly2032Asp substitution located on the same allele. In transfected cells, the Gly2032Asp mutation caused an approximately 2-fold reduction of the intracellular FV protein and a 9-fold reduction of the secreted protein, suggesting that the Gly2032Asp substitution acts in cis on the allele carrying the FVLeiden mutation and rescues the APC-resistance phenotype.