Sequence variation and genetic evolution at the human F12 locus: mapping quantitative trait nucleotides that influence FXII plasma levels.

The level of Factor XII (FXII) is an important phenotype that exhibits a high genetic component and is associated with thrombotic disease. In a genome-wide linkage scan, we demonstrated that the F12 gene represents a quantitative trait locus (QTL) that influences FXII levels. The current study investigated the genetic architecture of the F12 gene to locate polymorphism(s) responsible for the variation of FXII levels. Re-sequencing of the F12 gene in 40 unrelated individuals (selected from the tails of normal distribution of FXII levels) identified 26 polymorphisms which were genotyped in 398 individuals belonging to 21 families from the GAIT Project. By a measured genotype association analysis, eight of 26 SNPs showed significant P-values less than 10(-5) (after multiple test correction) with FXII levels. In addition, the Bayesian Quantitative Trait Nucleotide method, which infers those polymorphisms most likely to have a direct influence on the trait under study, provided evidence that only rs1801020 variation accounted for the variance attributed to this QTL. Moreover, we have analyzed the evolutionary processes that produced the variation in F12 gene and concluded that is evolutionarily neutral and that the T allele of the rs1801020 appeared approximately 100 000 years ago and spread to most human populations rising to high frequencies by genetic drift. Our study provides a template for future genetic studies of human quantitative traits, as we move beyond QTL localization to the polymorphisms responsible for the variation of important biomedical phenotypes.

C4BPB/C4BPA is a new susceptibility locus for venous thrombosis with unknown protein S-independent mechanism: results from genome-wide association and gene expression analyses followed by case-control studies.

Through its binding with protein S (PS), a key element of the coagulation/fibrinolysis cascade, the C4b-binding protein (C4BP) has been hypothesized to be involved in the susceptibility to venous thrombosis (VT). To identify genetic factors that may influence the plasma levels of the 3 C4BP existing isoforms, alpha(7)beta(1), alpha(6)beta(1), and alpha(7)beta(0), we conducted a genome-wide association study by analyzing 283 437 single nucleotide polymorphisms (SNPs) in the Genetic Analysis of Idiopathic Thrombophilia (GAIT) study composed of 352 persons. Three SNPs at the C4BPB/C4BPA locus were found genome-wide significantly associated with alpha(7)beta(0) levels. One of these SNPs was further found to explain approximately 11% of the variability of mRNA C4BPA expression in the Gutenberg Heart Study composed of 1490 persons, with no effect on C4BPB mRNA expression. The allele associated with increased alpha(7)beta(0) plasma levels and increased C4BPA expression was further found associated with increased risk of VT (odds ratio [OR] = 1.24 [1.03-1.53]) in 2 independent case-control studies (MARseille THrombosis Association study [MARTHA] and FActeurs de RIsque et de récidives de la maladie thromboembolique VEineuse [FARIVE]) gathering 1706 cases and 1379 controls. This SNP was not associated with free PS or total PS. In conclusion, we observed strong evidence that the C4BPB/C4BPA locus is a new susceptibility locus for VT through a PS-independent mechanism that remains to be elucidated.

Influence of age, gender and lifestyle in lymphocyte subsets: report from the Spanish Gait-2 Study.

INTRODUCTION: Flow cytometry analysis of lymphocyte subsets in peripheral blood is a common technique in diagnostic laboratories. Abnormal values have been identified in prevalent infections, autoimmune disorders and neoplastic diseases. Reference ranges for lymphocyte subsets of a healthy population from Spain are scarce. METHODS: The study was performed on 319 healthy subjects, aged 4-88 years, from 709 individuals enrolled in the GAIT-2 Project (Genetic Analysis of Idiopathic Thrombophilia). Health status, age, sex, fertility, BMI and lifestyle (physical activity, cigarette smoking and ethanol intake) were assessed using standardized criteria. The percentage of lymphocyte subsets was determined using flow cytometry (Lymphogram™). Percentages of CD3+, CD4+, CD8+, CD19+, CD3-CD56+, CD3+CD4-CD8- double-negative (DN) T cells, CD3+CD4+CD8+ double-positive T cells and the CD4+/CD8+ ratio were recorded for each case. RESULTS: Children had a significantly higher percentage of CD19+ and DN cells than adults. Women had a significantly higher percentage of CD3+ and CD4+ and a lower percentage of natural killer cells than men. Increases in BMI were inversely associated with the percentage of DN cells. Physical activity increased the percentage of lymphocytes and DN cells. Alcohol consumers had a lower percentage of CD19+ and DN cells, and a higher percentage of CD4+. CONCLUSION: This study provides reference ranges for lymphocyte subsets of healthy children and adults in a Mediterranean population (Spain) and determines the influence of lifestyle factors on these values.

Identification of ZNF366 and PTPRD as novel determinants of plasma homocysteine in a family-based genome-wide association study.

Total plasma homocysteine concentration (tHcy) is a biomarker for atherothrombotic disease, but causality remains uncertain. Polymorphisms in the genes involved in methionine metabolism explain only a small fraction of the heritability of tHcy levels. In a genome-wide association study, we examined the genetic determinants of tHcy using a 2-stage design. First, 283 437 single nucleotide polymorphisms (SNPs) were tested for association with tHcy in 387 persons recruited from 21 large Spanish families. Of those, 17 SNPs showed equal or stronger association with tHcy level compared with the MTHFR 677C>T SNP (beta = 0.10, P = .0001). Second, a replication analysis of these 17 SNPs was performed in patients with premature myocardial infarction (n = 1238). Novel associations were found for SNPs near the ZNF366 gene (lead SNP rs7445013; discovery stage: adjusted beta = -0.12, P = 5.30 x 10(-6), replication stage: adjusted beta = -0.13, P = .004) and the PTPRD gene (lead SNP rs973117; discovery stage: adjusted beta = 0.11, P = 5.5 x 10(-6), replication stage: adjusted beta = 0.10, P = .005). These associations were independent of known confounders, including creatinine clearance and plasma fibrinogen concentration. Our findings implicate novel pathways in homocysteine metabolism, and highlight the need for investigation of the associated genes in the etiology of vascular diseases.

Heritability of thromboxane A2 and prostaglandin E2 biosynthetic machinery in a Spanish population.

OBJECTIVE: Prostanoids play a critical role in clinical areas such as inflammation, thrombosis, immune response, and cancer. Although some studies suggest that there are genes that determine variability of some prostanoid-related phenotypes, the genetic influence on these traits has not been evaluated. METHODS AND RESULTS: The relative contributions of genetic and environmental influences to the prostanoid biosynthetic pathway-related phenotypes, cyclooxygenase isoenzymes, microsomal-PGE-synthase-1 and TxA-synthase expression, and thromboxane-A(2) and prostaglandin-E(2) production by stimulated whole blood, were assessed in a sample of 308 individuals in 15 extended families. The effects of measured covariates (such as sex, age, and smoking), genes, and environmental variables shared by members of a household were quantified. Heritabilities ranging from 0.406 to 0.634 for enzyme expression and from 0.283 to 0. 751 for prostanoid production were found. CONCLUSIONS: These results demonstrate clearly the importance of genetic factors in determining variation in phenotypes that are components of the prostanoid biosynthetic pathways. The presence of such strong genetic effects suggest that it will be possible to localize previously unknown genes that influence quantitative variation in these phenotypes, some of which affect multiple aspects of cell biology, with important clinical implications.

Platelet hyperaggregability and venous thrombosis risk: results from the RETROVE project.

The aim of the study was to determine whether platelet hyperaggregability correlates with short closure times (PFA-100) and if hyperaggregability is associated with the risk of venous thrombosis in a Spanish population. Case--control study (RETROVE project) involving 400 patients with venous thrombosis and 400 healthy controls. We determined platelet aggregation in platelet-rich plasma (PRP) by light transmission aggregometry. Various concentrations of two aggregation agonists [ADP and epinephrine (EPI)] were tested to determine the percentage of maximal aggregation and the percentage area under the curve (AUC). Venous thrombosis risk associated with platelet hyperaggregability was calculated by logistic regression. We estimated the crude and adjusted (by sex and age) odds ratios (OR) for venous thrombosis risk. An agonist concentration of 0.5 µmol/l differentiated between hypo-responders and hyper-responders at the following AUC cut-off values: EPI: the 50th percentile for aggregation with 0.5 µmol/l of EPI (EPI_AUC) was 22.53% (>22.53% = hyper-EPI); the crude risk for venous thrombosis was statistically significant (OR = 1.37; 95% CI 1.03-1.82); ADP: the 75th percentile for aggregation with 0.5 µmol/l of ADP (ADP_AUC) was 29.6% (>29.6% = hyper-ADP), with a significant crude risk for venous thrombosis (OR = 1.44; 95% CI 1.05-1.98). However, after adjustment for confounders (age), the ORs for EPI or ADP aggregation were no longer significant. EPI_AUC and PFA-100 values with the EPI agonist were significantly correlated (R = -0.342, P < 0.01). Only 12% of the PFA-100 values were explained by platelet aggregation. In this case--control study, platelet hyperaggregability was not associated with the risk of developing venous thrombosis.

Hemostatic proteins and their association with hematoma growth in patients with acute intracerebral hemorrhage.

BACKGROUND AND PURPOSE: We tested the hypothesis that proteins of hemostasia could be associated with hematoma growth (HG) in patients with acute intracerebral hemorrhage. METHODS: We prospectively studied patients with spontaneous supratentorial intracerebral hemorrhage within the first 6 hours after the onset of symptoms. HG was defined as an increase > 33% in the volume of hematoma on CT obtained 24 to 72 hours after the onset of symptoms in comparison with the CT obtained at admission. We collected admission and follow-up blood samples. We measured fibrinogen, factor XIII, thrombin activatable fibrinolysis inhibitor, plasminogen activator inhibitor, plasminogen, α2-antiplasmin, tissue plasminogen activator, d-dimer, thrombomodulin, thrombin-antithrombin complex, and plasmin-antiplasmin complex. RESULTS: We included 90 patients with a mean age of 71 ± 10.8 years; 61% were men. HG was observed in 35 (39%) of the patients. Mean baseline and follow-up protein measurements showed no difference between the groups with and without HG. The analysis of variance showed that factor XIII activity decreased in the non-HG group in the 24 to 72 hours sample, whereas it increased in the HG group (P = 0.001). CONCLUSIONS: Factor XIII was the only measured protein related to HG. The levels at the follow-up sample decreased in the non-HG group and increased in the HG group. Further studies are needed to confirm this association.

Antithrombin Cambridge II (A384S) supports a role for antithrombin deficiency in arterial thrombosis.

Although the control of thrombin in the microvasculature at the endothelial cell surface is crucial to prevent atherothrombosis, the role of antithrombin in arterial thrombosis is unclear. It is widely considered that antithrombin deficiency is unlikely to contribute to arterial thrombosis, but no convincing epidemiological study has been performed because of the low frequency of this deficiency. In this study we evaluated the role in myocardial infarction (MI) of a relatively common mutation affecting antithrombin gene (A384S: Antithrombin Cambridge II) that has functional features that may impair the right control of thrombogenic events caused by injury to the vascular wall. Moreover, this deficiency, which is not detected using common methods to diagnose antithrombin deficiency, also increases the risk of venous thrombosis. We included 1,224 patients with MI (691 consecutive patients and 533 survivors of a premature event), and 1,649 controls. The mutation was identified in 0.3% of controls, but 0.8% of MI patients. After adjusting for sex and other cardiovascular risk factors, the antithrombin Cambridge II significantly increased 5.66-fold the risk of MI (95% CI: 1.53-20.88; p = 0.009). Interestingly, young patients had the highest risk of MI associated with the mutation (OR: 9.98; 95%CI: 1.60-62.24; p = 0.009). This is the first epidemiological study that supports a role for antithrombin deficiency in arterial thrombosis. These results suggest that deficiency of antithrombin may be an independent risk factor for MI that has been underestimated, but larger studies are needed to confirm the relevance of inhibitors of thrombin in arterial thrombosis.

VAMP8 and serotonin transporter levels are associated with venous thrombosis risk in a Spanish female population. Results from the RETROVE Project.

INTRODUCTION: Platelet hyper-reactivity has been associated with thrombosis and high levels of human vesicle-associated membrane protein 8 (VAMP8) and serotonin transporter (SERT). Two polymorphisms (rs1010 of VAMP8 gene and in SERT gene (SLC6A4)) are associated with arterial thrombosis. AIM: To determine if levels of serotonin, SERT and/or VAMP8 and these polymorphisms are associated with the risk of venous thrombosis. MATERIAL AND METHODS: A total of 324 individuals were included in the RETROVE Study (Riesgo de Enfermedad TROmboembólica VEnosa). VAMP8, SERT and serotonin were determined by ELISA; polymorphisms of SLC6A4 and VAMP8 by polymerase chain reaction (PCR) and real time PCR. The venous thrombotic risk was calculated by a logistic regression method to estimate the crude and adjusted OR (adjusted for sex, age, body mass index and venous thrombosis risk co-factors). RESULTS: Statistically significant high levels of VAMP8 and SERT were found in patients, but not in controls. In contrast, serotonin showed lower levels in patients than in controls. When individuals were studied by gender, only women exhibited a statistically significant difference: the OR for VAMP8 was 3.25 (1.61-6.56 95% CI). The adjusted OR did not change. The OR for SERT was 2.76 (1.36-5.60 95% CI), the adjusted OR was maintained also. For serotonin with OR of 2.62 (1.40-4.92 95% CI), the adjusted OR was not significant. In contrast males did not show significant differences. No statistically differences between patients and controls were found for both polymorphisms. CONCLUSIONS: VAMP8 and SERT levels are associated with venous thrombosis in a female Spanish population.

Change in hemostatic markers after recombinant tissue-type plasminogen activator is not associated with the chance of recanalization.

BACKGROUND AND PURPOSE: We evaluated the association between recombinant tissue-type plasminogen activator recanalization and change in hemostatic markers. METHODS: We studied 40 patients. Recanalization was measured with transcranial Doppler. We evaluated the change in markers of coagulation (fibrinogen) and fibrinolysis (thrombin activatable fibrinolysis inhibitor and alpha(2)-antiplasmin) in patients with ischemic stroke treated with recombinant tissue-type plasminogen activator. Samples were obtained before and 90 minutes after recombinant tissue-type plasminogen activator infusion. RESULTS: The analyses (2-way analysis of variance) showed that the change in the value of each marker did not depend on the vascular patency status. CONCLUSIONS: From a practical point of view, the measurement of these hemostatic markers is probably not useful for predicting recanalization.

Genome-wide linkage analysis for identifying quantitative trait loci involved in the regulation of lipoprotein a (Lpa) levels.

Lipoprotein Lp(a) levels are highly heritable and are associated with cardiovascular risk. We performed a genome-wide linkage analysis to delineate the genomic regions that influence the concentration of Lp(a) in families from the Genetic Analysis of Idiopathic Thrombophilia (GAIT) Project. Lp(a) levels were measured in 387 individuals belonging to 21 extended Spanish families. A total of 485 DNA microsatellite markers were genotyped to provide a 7.1 cM genetic map. The variance component linkage method was used to evaluate linkage and to detect quantitative trait loci (QTLs). The main QTL that showed strong evidence of linkage with Lp(a) levels was located at the structural gene for apo(a) on chromosome 6 (LOD score=13.8). Interestingly, another QTL influencing Lp(a) concentration was located on chromosome 2 with an LOD score of 2.01. This region contains several candidate genes. One of them is the tissue factor pathway inhibitor (TFPI), which has antithrombotic action and also has the ability to bind lipoproteins. However, quantitative trait association analyses performed with 12 SNPs in TFPI gene revealed no association with Lp(a) levels. Our study confirms previous results on the genetic basis of Lp(a) levels. In addition, we report a new QTL on chromosome 2 involved in the quantitative variation of Lp(a). These data should serve as the basis for further detection of candidate genes and to elucidate the relationship between the concentration of Lp(a) and cardiovascular risk.

A genome-wide exploration suggests an oligogenic model of inheritance for the TAFI activity and its antigen levels.

Thrombin-Activatable Fibrinolysis Inhibitor (TAFI) is a protein that potently attenuates fibrinolysis. A considerable proportion of its variability levels is genetically determined. It has been associated with arterial and venous thrombosis. We conducted a Genome Wide Scan for genes affecting variation in plasma TAFI levels in 398 subjects from 21 extended Spanish families. The data were analyzed by a variance-component linkage method. A strong linkage signal was found on the long arm of Chromosome 13, near the DNA marker D13S156, where the structural gene encoding for TAFI is located. In addition, other new linkage signals were detected on chromosome regions 5p and 7q. More importantly, we performed another multipoint linkage analysis of functional TAFI conditioned on TAFI antigen levels. We detected a strong linkage signal on Chromosome 19 (LOD = 3.0, P = 0.0001) suggesting a novel QTL in this region involved in the specific functional activity of TAFI, regardless of the TAFI antigen levels. One notable aspect of this study is the identification of new QTLs that reveal a clearer picture of the genetic determinants responsible for variation in TAFI levels. Another is the replication of the linkage signal of the CPB2 gene, which confirms an important genetic determinant for TAFI antigen levels. These results strongly suggest an oligogenic mode of inheritance for TAFI, in which CPB2 gene accounts for a proportion of the variation of the phenotype together with other unknown genes that may represent potential risk factors for thrombotic disease.

Fibrinolytic inhibitor levels and polymorphisms in Behçet disease and their association with thrombosis.

This study aimed to assess the fibrinolytic inhibitors and their association with thrombosis in Behçet disease. Thrombin activatable fibrinolysis inhibitor (TAFI) (P < 0.001) and plasminogen activator inhibitor-1 (PAI-1) levels (P = 0.022) were significantly higher in 79 patients than in 84 controls. No significant differences were observed in CPB2 (TAFI) Thr325Ile and SERPINE1 (PAI1) 4G/5G polymorphism distribution between patients and controls. TAFI activity levels were significantly higher in patients with thrombosis than in those without thrombosis (P = 0.024). In conclusion, the increased TAFI levels in Behçet disease could contribute to the increased risk of thrombosis observed in these patients.

AB0 blood group and risk of venous or arterial thrombosis in carriers of factor V Leiden or prothrombin G20210A polymorphisms.

BACKGROUND: Routine analyses for thrombophilia include determination of the presence of factor V Leiden and prothrombin 20210A polymorphisms. However, the usefulness of these determinations is controversial and the clinical benefit remains questioned because of the moderate risk of associated thrombosis in carriers. In the search for clusters of thrombotic risk factors to estimate individual risk better, we studied the effect of AB0 blood group, a highly prevalent factor with mild prothrombotic features, on the risk and severity of venous and arterial thromboses in carriers of these polymorphisms. DESIGN AND METHODS: We genotyped the AB0 blood group in 981 carriers of factor V Leiden or prothrombin 20210A polymorphisms. In order to avoid the over-representation of a particular genotype and to suppress confounding factors, we included only non-related heterozygous carriers without additional genetic risk factors. We studied 609 patients with venous thromboembolism (287 with factor V Leiden, and 322 with prothrombin 20210A), 174 patients with myocardial infarction (78 with factor V Leiden, and 96 with prothrombin 20210A), and 198 controls (96 with factor V Leiden, and 102 with prothrombin 20210A). RESULTS: Non-OO blood group did not increase the risk of myocardial infarction in carriers of factor V Leiden or prothrombin 20210A. However, non-OO blood group contributed significantly to the expression of venous thrombosis associated with both factor V Leiden (OR: 1.76; 95%CI: 1.06-2.91) and prothrombin 20210A (OR: 2.17; 95%CI: 1.33-3.53). Exclusion of A(2)A(2) and A(2)O from the non-00 blood group (because factor VIII-von Willebrand factor levels are similar in these and the 00 blood group) increased the thrombotic risk. Finally, non-OO blood group was associated with an earlier onset in symptomatic carriers of these polymorphisms. CONCLUSIONS: Our study suggests that non-OO blood group increases the risk and severity of venous thrombosis in carriers of prothrombotic polymorphisms. Thus, AB0 phenotyping or genotyping analyses may be valuable components in assessing future thrombophilic risk profiles and might have implications for the policy of thrombosis prophylaxis and treatment.

Evaluation of the effectiveness and safety of bemiparin in a large population of orthopedic patients in a normal clinical practice.

The authors conducted a prospective, open, multicenter, observational study to audit the utilization patterns of bemiparin in orthopedic patients in daily clinical practice. They analyzed rates of documented symptomatic venous thromboembolism (VTE) (deep vein thrombosis and pulmonary embolism) confirmed by objective methods, major bleeding, death, thrombocytopenia, and other adverse events. It was also intended to analyze the influence of concomitant factors (bemiparin dose, concomitant medications, age, and obesity) on VTE and bleeding rates. A total of 7959 patients were included and received bemiparin for 28 days (median). Bemiparin 3500 IU/d was used in 84.9% of patients, whereas bemiparin 2500 IU/d was administered to 15.1% of patients. Reason for prophylaxis (number of cases [%]) included cast immobilization of the leg (2052 [25.8%]), knee replacement (1082 [13.6%]), hip replacement (876 [11.0%]), hip fracture surgery (437 [5.5%]), other lower limb surgery (1569 [19.7%]), knee arthroscopy (769 [9.7%]), and spine surgery (231 [2.9%]). A total of 943 patients with insufficient data on reason for prophylaxis and 560 patients with no outcome assessment were excluded from the analysis of clinical outcomes. Among 6456 assessable patients, the authors found a low rate of documented symptomatic VTE (0.91%), major bleeding (0.17%), deaths (0.37%), and mild to moderate thrombocytopenia (0.51%). None of the major bleedings was fatal or occurred in a critical organ. There were 3 deaths in which fatal pulmonary embolism (PE) could not be ruled out. There were no cases of severe type-II thrombocytopenia. VTE rates were not increased in obese patients, and major bleeding rates were not increased in elderly patients or in patients taking nonsteroidal anti-inflammatory drugs. In conclusion, bemiparin prophylaxis, given for 3 to 4 weeks in cast immobilization of the leg and other orthopedic procedures, was associated with low rates of VTE, bleeding, and other adverse events in normal clinical practice.

[Oral anticoagulat treatment in venous thromboembolic disease]. / Anticoagulación oral en enfermedad tromboembólica.

Coumarin or anti-vitamin K oral anticoagulants have been used in anticoagulation therapy for more than 50 years. Well-designed studies have demonstrated the effectiveness of these drugs in the primary and secondary prevention of venous thromboembolic disease (VTD). Because of greater life expectancy and the increase in the indications for oral anticoagulation therapy (OAT), more and more patients are receiving this type of treatment. In Spain, approximately 1% of the population receives OAT. The mechanism of action of coumarin anticoagulants is based on inhibition of the interconversion of vitamin K and its 2,3-epoxide (vitamin K epoxide, which modulates gamma-carboxylation of the glutamic acid residues in the N-terminal regions of vitamin-K-dependent factors, namely, II, VII, IX, X, protein C, protein S and protein Z). Due to the lack of gamma-carboxylation, these factors lose their procoagulant activity. Major hemorrhagic complications of OAT in VTD after 3-6 months of treatment, with an INR of 2-3, occur in nearly 2% of patients. The hemorrhagic complications of OAT are related to the intensity of anticoagulation, patient characteristics, the concomitant use of drugs that interfere with hemostasis, and treatment duration. The risk of VTD recurrence after 3-6 months of OAT is high and can be more than 10% in patients with idiopathic thromboembolism or irreversible risk factors such as thrombophilia, cancer and other situations conferring permanent risk. The risk of recurrence is more frequent in men, in patients with thrombophilia especially in antithrombin deficiency, and in patients with cancer, residual venous obstruction, or elevated D dimer.

Short closure time values in PFA-100® are related to venous thrombotic risk. Results from the RETROVE Study.

INTRODUCTION: Platelets play a role in the pathophysiology of venous thromboembolism (VTE). Some studies have not found an association between VTE and platelet aggregation. The PFA-100® analyser is an in vitro assay for assessing primary haemostasis. But, there are no studies to evaluate its association with VTE. We investigated the contribution of the global platelet function and aggregation in the development of VTE. MATERIAL AND METHODS: We analysed 800 individuals who were included in the RETROVE Study (Riesgo de Enfermedad TROmboembólica VEnosa). Global platelet function was evaluated as closure times (CT) with the agonists ADP and epinephrine using a PFA-100® analyser. Platelet aggregation was evaluated by Multiplate™ analyser. The VTE risk for all the parameters was calculated by unconditional logistic regression analyses considering the potential confounders: age, gender, body mass index (BMI), factor VIII (FVIII), the von Willebrand factor (vWF) and the ABO blood group system. RESULTS: The unadjusted odds ratio (OR) values ≤10th percentile for the PFAadp and PFAepi were 4.02 (95% CI, 2.76-5.95) and 3.33 (2.27-4.97). Also, after adjusting for vWF, we obtained lower OR for the PFAadp and for PFAepi: 2.24 (1.44-3.49) and 1.63 (1.04-2.59). But, the whole blood aggregation parameters did not shown an association with VTE risk. CONCLUSION: We demonstrated an association between short CT and VTE risk. Although, the whole blood aggregation parameters did not show an association with the VTE risk. This striking contrast suggests that there are other platelet function mechanisms (e.g. adhesion) that are responsible of VTE risk.

Molecular analysis of multiple genetic variants in Spanish FXII-deficient families.

We studied 3 Spanish patients with <1% FXII levels. DNA sequencing of the whole F12 gene identified 15 genetic variants. Molecular analyses of F12 mRNA demonstrated that the deficiency was caused by 5281delG in exon 9 of Patient 1 (in the homozygous state) and the 6306delG in exon 12 and another deletion of 23 bp in intron 8 of Patient 2 (both in the heterozygous state). Finally, a G-8C transversion was found in the homozygous state in Patient 3. Based on previous data, including a mouse model, the G-8C might be responsible for the FXII deficiency. None of these variants were present in 40 controls.

The V617F mutation of JAK2 is very uncommon in patients with thrombosis.

Given that many cases of thrombosis do not have a clear cause, a myeloproliferative disease could be involved. We investigated the V617F mutation of the JAK2 gene in 295 patients with thrombosis. Only one case was positive. Therefore, the study of this mutation is not necessary in all patients with idiopathic thrombosis.