Valoración de la presión pulmonar y su repercusión sobre cavidades derechas por ecocardiografía / No disponible

El presente capítulo tiene como objetivo acercar al neumólogo el conocimiento de la ecocardiografía como herramienta fundamental para la estimación de parámetros hemodinámicos de indudable importancia para el agnóstico, la estratificación del riesgo y el manejo terapéutico de la hipertensión pulmonar (HTP) y el tromboembolismo pulmonar (TEP). En general, estas mediciones ecocardiográficas muestran una excelente correlación con la hemodinámica y los métodos empleados no son excesivamente complejos, estando al alcance de cualquier profesional con un tiempo de adiestramiento muy razonable. Este texto trata de explicar, de forma gráfica y sencilla, los distintos métodos empleados en ecocardiografía para cuantificar la presión pulmonar y las resistencias vasculares pulmonares. La ecocardiografía valora, además, las repercusiones que la HTP y el TEP ejercen sobre las cavidades derechas en su intento de adaptación, permitiéndonos analizar los principales parámetros de morfología y función ventricular derecha, que han demostrado tener un valor pronóstico en estas patologías

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Genetic determinants of plasma ß2-glycoprotein I levels: a genome-wide association study in extended pedigrees from Spain.

BACKGROUND: ß2 -Glycoprotein I (ß2 -GPI), also designated apolipoprotein H, is a 50-kDa protein that circulates in blood at high concentrations, playing important roles in autoimmune diseases, hemostasis, atherogenesis, and angiogenesis, as well as in host defense against bacteria and in protein/cellular waste removal. Plasma ß2 -GPI levels have a significant genetic component (heritability of ~ 80%). OBJECTIVES: To present the results of a genome-wide association study for plasma ß2 -GPI levels in a set of extended pedigrees from the Genetic Analysis of Idiopathic Thrombophilia (GAIT) Project. PATIENTS/METHODS: A total of 306 individuals for whom ß2 -GPI plasma measurements were available were typed for 307,984 single-nucleotide polymorphisms (SNPs) with the Infinium 317k Beadchip (Illumina). Association with the ß2 -GPI phenotype was investigated through variance component analysis, and the most significant results were followed up for association with coronary artery disease (CAD) in an independent in silico analysis involving 5765 CAD cases from the PROCARDIS Project and 7264 controls from the PROCARDIS Project and the Wellcome Trust Case Control Consortium (WTCCC) collection. RESULTS: After correction for multiple testing, three SNPs located in/around two genes (ELF5 and SCUBE2) reached genome-wide significance. Moreover, an SNP in the APOH gene showed suggestive association with the ß2 -GPI phenotype. Some of the identified genes are plausible biological candidates, as they are actually or potentially involved in inflammatory processes. CONCLUSIONS: Our results represent a first step towards identifying common variants reflecting the genetic architecture influencing plasma ß2 -GPI levels, and warrant further validation by functional experiments, as the functions of some of the discovered loci are still unknown.

Comparative pharmacodynamic time-course of bemiparin and enoxaparin in healthy volunteers.

UNLABELLED: Low-molecular-weight heparins (LMWHs) are antithrombotic drugs that differ on biochemical and pharmacological properties. OBJECTIVE: This study was conducted to compare the pharmacodynamic time-course of two LMWHs, bemiparin and enoxaparin, at high prophylactic doses. METHODS: This was an open, randomized, single-blind, cross-over study to compare the pharmacodynamic time-course, safety and tolerability of two LMWHs, bemiparin 3500 IU and enoxaparin 4000 IU at subcutaneous single doses in 12 healthy male volunteers. Anti-Xa activity (main biomarker of heparin activity), anti-IIa activity, total and free tissue factor pathway inhibitor (TFPI), activated partial thromboplastin time (APTT), thrombin time (TT) and thromboplastin-thrombomodulin mediated time (Tp-TmT) were investigated. RESULTS: Bemiparin 3500 IU achieved more anti-Xa activity than enoxaparin 4000 IU, measured by the area under the curve (geometric mean AUC0t) (bemiparin 3.69 vs. enoxaparin 3.33 IU h/ml; p < 0.001). Maximum anti-Xa activity was reached at 3 hours and there were anti-Xa measurable levels up to 16 h after subcutaneous administration. Anti-Xa activity half-life was 5.44 hours for bemiparin and 4.71 hours for enoxaparin. Anti-IIa activity was above the limit of quantification (0.05 IU/ml) in only 2 volunteers after bemiparin and in 8 after enoxaparin. The "in-vivo" anti-Xa:IIa ratios were: bemiparin 37.9 (95% CI: 28.0 - 55.3, n = 2) and enoxaparin 16.3 (95% CI: 12.2 - 23.4, n = 8). Enoxaparin induced a higher release of total TFPI, but not on free TFPI, and a longer prolongation of APTT and TT (Emax) than bemiparin, with no differences between groups on Tp-TmT. Adverse events (one in each group) were mild and transient. CONCLUSION: Bemiparin 3500 IU showed more anti-Xa activity and higher anti-Xa: anti-IIa relationship than enoxaparin 4000 IU in healthy volunteers. Both treatments were well tolerated.

Higher risk of ischaemic stroke associated with factor XI levels in dyslipidaemic patients.

BACKGROUND: Ischaemic stroke (IS) is a complex disease that involves genetic and environmental factors. The role of factor XI (FXI) in arterial thrombosis is unclear. We have investigated the risk of IS related to FXI levels in a case-control study. METHODS: We studied 445 individuals: 218 diagnosed with IS and 227 age-gender-ethnic matched control subjects. We measured factor VIIIc, fibrinogen and factor XIc levels. FXI < 144% was taken as the reference group in the statistical analysis. RESULTS: There were 104 women and 114 men in the IS group and 108 women and 119 men in the control group. The crude odds ratio (OR) of IS in dyslipidaemic patients with high levels of FXI was 4.2 [95% confidence interval (CI): 1.2-14.8] compared with dyslipidaemic controls and low levels of FXI, but the OR in the non-dyslipidaemic with high levels of FXI subgroup was 1.2 (95% CI: 0.4-3.2). The adjusted OR of IS in dyslipidaemic patients with high levels of FXI was 6.4 (95% CI: 1.6-26.1) compared with dyslipidaemic controls, but the OR in non-dyslipidaemic subgroup with high levels of FXI was 0.6 (95% CI: 0.2-2.1). CONCLUSION: We found almost a sixfold higher risk of IS in patients with dyslipidaemia and high levels of FXI. Further studies should elucidate the role of FXI in IS and therapeutic approaches should become apparent for patients with dyslipidaemia and high-FXI plasma levels.

An acquired inhibitor that produced a delay of fibrinopeptide B release in an asymptomatic patient.

An asymptomatic, 29-year-old woman was referred to our hospital before surgery because in the basic study of hemostasis she showed a prolonged thrombin time (TT) and a normal reptilase time (RT). She had not received any anticoagulants so, to account for these abnormal results the presence of an inhibitor or a dysfibrinogenemia was suspected. A 1:1 mixture of the patient's plasma with control plasma did not correct the TT. Dysfibrinogenemia was excluded because the defibrinated plasma retained the inhibitory activity when mixed with normal plasma. When 0.02 mg/ml of Protamine Sulphate (a concentration that neutralizes 1 U/mL of heparin in normal plasma) was added to the patient's plasma, the inhibitory activity did not disappear. IgG from the patient and from normal serum was isolated. The patient's IgG was able to prolong the TT of a normal plasma and of a purified fibrinogen. The patient IgG did not impair the catalytic activity of thrombin, because no difference was observed in the hydrolysis of S-2238 by 1 U NIH human thrombin with normal or patient IgG. The time course of the thrombin-mediated fibrinopeptide-release from normal fibrinogen with the patient's IgG, showed a delay in the fibrinopeptide B (FPB) release without affecting the fibrinopeptide A (FPA) release. This patient has an IgG antibody that delays fibrinopeptide B release of fibrinogen.

Diagnostic yield of prothrombotic state studies in cryptogenic stroke.

OBJECTIVES: Around 30% of ischemic strokes are considered cryptogenic. We analyzed the diagnostic yield of prothrombotic state (PS) studies in patients with an initial cryptogenic stroke (CS). MATERIAL AND METHODS: We prospectively included consecutive CS patients according to the TOAST criteria. PS included plasmatic determinations of antiphospholipid (APL) antibodies and lupus anticoagulant (LA), S (SPd) and C (CPd) protein deficiencies, and genetic analysis of the prothrombin gene mutation (PT G20210A) and the factor V Leiden mutation (FV G1691A). We recorded age, sex and vascular risk factors. RESULTS: From a total of 89 patients (mean age 56.9 +/- 14.3 years, 53% men), we identified 16 PS in 15 patients (16.85%): APL-6, LA-2, SPd-2, CPd-1, PT G20210A -3 and FV G1691A -2. One patient presented an association (APL and PT G20210A). CONCLUSIONS: One of every six patients with initial CS present a PS. Age or sex and conventional cardiovascular risk factors were not related to PS study findings, supporting the relevance of such studies in all patients with an initial CS.

Hemostatic markers of recanalization in patients with ischemic stroke treated with rt-PA.

OBJECTIVE: To determine whether pretreatment markers of coagulation and fibrinolysis are related to recanalization and functional outcome. METHODS: The authors included patients treated with IV rt-PA with occlusion on baseline transcranial Doppler (Thrombolysis in Brain Ischemia [TIBI] criteria) in whom recanalization within 6 hours was monitored. At baseline, the authors recorded data about demographics, vascular risk factors, the NIH Stroke Scale (NIHSS) score, early CT signs, etiology, blood glucose, and time to rt-PA. The authors also measured plasmatic markers of coagulation (fibrinogen, prothrombin fragments 1 + 2, Factor XIII, Factor VII) and fibrinolysis (alpha2-antiplasmin, Plasminogen Activator Inhibitor, Functional Thrombin Activatable Fibrinolysis Inhibitor [fTAFI]). A favorable outcome was defined as a modified Rankin score < 2 at 3 months. RESULTS: The authors studied 63 patients with a mean age of 67.3 +/- 12.5 years. The median NIHSS score was 16. Patients who recanalized had lower concentrations of alpha2-antiplasmin (87.5 +/- 18% vs 96.5 +/- 12.5%, p = 0.023) and fTAFI (91.7 +/- 26.7% vs 104.4 +/- 21%, p = 0.039). A multivariant logistic regression analysis showed that the level of alpha2-antiplasmin was the only predictive variable of recanalization (OR 0.95, 95% CI 0.91, 0.99, p = 0.038), while the NIHSS score was the only predictive variable of functional outcome (OR 0.81, 95% CI 0.72, 0.92, p = 0.001). CONCLUSION: Baseline levels of alpha2-antiplasmin were predictive of recanalization but were not related to the long-term outcome in patients treated with rt-PA within the first 3 hours.

A locus on chromosome 2 influences levels of tissue factor pathway inhibitor: results from the GAIT study.

OBJECTIVE: Levels of tissue factor pathway inhibitor (TFPI) have been associated with arteriosclerosis and thrombotic disease. Although a genetic component to variation in TFPI levels is well-documented, no systematic genome-wide screens have been conducted to localize genes influencing levels of TFPI. METHODS AND RESULTS: We studied TFPI levels in 397 individuals in 21 Spanish families participating in the Genetic Analysis of Idiopathic Thrombosis (GAIT) study. Twelve families were selected through a proband with idiopathic thrombosis and 9 were ascertained without regard to phenotype. A genome scan was performed using microsatellite markers spaced at approximately 10 cM intervals. Standard multipoint variance component linkage methods were used. The heritability of TFPI levels was 0.52 (P<0.0001), with no evidence for shared household effects. In the genome screen, only 1 LOD score >2 was observed. On chromosome 2q, the maximum multipoint LOD score was 3.52 near marker D2S1384. This is near the structural gene for TFPI, which is located at 2q32. In follow-up association analyses, marginal evidence of association (P=0.04) was observed with the TFPI promoter variant C-399T. CONCLUSIONS: These results suggest that polymorphisms in and around the TFPI structural gene may be the major genetic determinants of variation in TFPI levels.

Risk of ischemic stroke associated with functional thrombin-activatable fibrinolysis inhibitor plasma levels.

BACKGROUND AND PURPOSE: Recently, a novel procarboxypeptidase B-like proenzyme, called thrombin-activatable fibrinolysis inhibitor (TAFI), has been described. It plays an important role in the delicate balance between coagulation and fibrinolysis. TAFI leads to potent inhibition of tissue plasminogen activator-induced fibrinolysis. The relevance of TAFI in thromboembolic disease is unclear. We have investigated the risk of ischemic stroke (IS) in relation to plasma levels of functional TAFI. METHODS: In a case-control study, we enrolled 264 individuals; 114 had IS, and 150 were recruited as controls who were age and sex matched and had no history of arterial disease. The individuals supplied information on their personal and family histories of cardiovascular diseases and conventional cardiovascular risk factors. Functional TAFI assays were performed by use of a method based on the activation of TAFI with thrombin-thrombomodulin and the measure of the TAFI activity generated. Other hemostatic parameters assayed were factor VIIIc, anti-phospholipid antibodies,fibrinogen, factor V Leiden, and the prothrombin gene G20210A mutations (PT20210A). RESULTS: Functional TAFI levels were significantly higher in patients with IS (113.7+/-25%; range, 57% to 209%) than in controls (102.6+/-19%). The odds ratio for IS in patients with functional TAFI levels >120% was 5.7 (95% confidence interval, 2.3 to 14.1). CONCLUSIONS: We found that functional TAFI levels in plasma (>120%) increased the risk of IS approximately 6-fold. Further studies should elucidate the physiological role of TAFI in arterial disease and possibly provide clues to therapeutic approaches.

Comparative study of the pharmacokinetic profiles of two LMWHs--bemiparin (3500 IU, anti-Xa) and tinzaparin (4500 IU, anti-Xa)--administered subcutaneously to healthy male volunteers.

Pharmacokinetic profiles of bemiparin (3500 IU, anti-Xa) and tinzaparin (4500 IU, anti-Xa) administered subcutaneously to 12 healthy male volunteers were compared in a monocentric study. Each of the 12 subjects underwent successively the two low-molecular-weight heparin (LMWH) preparations in a randomised order and was considered as its own control. Anti-Xa activity, free and total tissue factor pathway inhibitor (TFPI), and thromboplastin-thrombomodulin-mediated time were determined as main variables. Activated partial thromboplastin time (APTT), thrombin clotting time, and anti-IIa activity were also determined. Bemiparin (3500 IU, anti-Xa) exerts a significantly more rapid, more potent, and more prolonged anti-Xa activity than tinzaparin (4500 IU, anti-Xa). The plasma level increase for free and total TFPI is significantly lower with bemiparin than with tinzaparin. Free and total TFPI peak levels occur earlier than anti-Xa activity peak levels for both LMWH preparations, but no statistical difference appeared between the two preparations for TFPI T(max). No significant effect was observed for both preparations for thromboplastin-thrombomodulin-mediated time. Subcutaneous injection of bemiparin exerts only minimal anti-IIa activity and does not prolong thrombin time, whereas tinzaparin elicits significant anti-IIa activity and prolongs thrombin clotting time. Bemiparin exerts a significantly lower prolongation of APTT than tinzaparin. No difference was observed for APTT prolongation T(max) between the two preparations. Globally, the overall tolerability of both formulations revealed no relevant adverse effects. In conclusion, bemiparin and tinzaparin are not bioequivalent. Bemiparin exerts an important and more prolonged anti-Xa activity in comparison with tinzaparin. An original finding of this study is the difference observed between the two formulations for free TFPI release.

Contribution of prothrombin 20210A allele and factor V Leiden mutation to thrombosis risk in thrombophilic families with other hemostatic deficiencies.

BACKGROUND AND OBJECTIVES: The aims of this study were to compare the lifetime probability of developing thrombosis in 722 relatives of 132 thrombophilic families of symptomatic probands with recognized thrombophilic defects and to determine the prevalence of the factor V Leiden (FVL) mutation and the 20210A allele of the prothrombin gene (PT20210A) in these families. DESIGN AND METHODS: The study included 722 members belonging to 132 unrelated families. The propositi were patients who had been referred to our Thrombosis Unit. The families were selected through a symptomatic proband. Once a patient with a deficiency or mutation was identified, family members were screened for the same defect. RESULTS: The prevalence of FVL and PT20210A in families with other thrombophilic defects was higher than expected. Compared with non-deficient individuals, the risk of venous thrombosis was increased in subjects with antithrombin (AT), protein S (PS) and protein C (PC) deficiencies, and in carriers of FVL and PT20210A mutations. The risk of thrombosis was significantly increased for individuals with combined genetic defects (PC-FVL, PS-FVL, PS-PT20210A and FVL-PT20210A). The ages at the time of 50% thrombosis-free survival were as follows: 34 years for AT deficiency, (19 years with FVL, 21 years with PT20210A), 62 years for PC deficiency (33 years with FVL, 44 years with PT20210A), 37 years for PS deficiency (24 years with FVL, 36 years with PT20210A), 50 years for the FVL mutation (52 years with PT20210A), and 65 years for the PT20210A mutation. As for clinical characteristics, no differences were observed except for the higher frequency of oral contraceptive-related thrombosis in women who were carriers of PT20210A or FVL. INTERPRETATION AND CONCLUSIONS: Based on these results, screening for FVL and PT20210A mutation is recommended in patients with other thrombophilic defects. To the best of our knowledge, this is the first family study, including the PT20210A mutation, that compares genetic risk factors for thrombosis and the lifelong probability of developing thrombosis.

Risk of thrombosis associated with oral contraceptives of women from 97 families with inherited thrombophilia: high risk of thrombosis in carriers of the G20210A mutation of the prothrombin gene.

BACKGROUND AND OBJECTIVES: Oral contraceptives (OC) and inherited thrombophilia are well-known risk factors associated with venous thromboembolism (VTE). However, there are only few studies on the risk of VTE in women with inherited thrombophilia who use oral contraceptives. DESIGN AND METHODS: We performed a retrospective family cohort study of 325 women belonging to 97 families with inherited thrombophilia, including antithrombin, protein S and C deficiencies, the factor V Leiden mutation (FVL) and the G20210A mutation of the prothrombin gene (PT20210A) to determine the risk of VTE associated with OC intake. RESULTS: For carriers of the PT20210A mutation, the risk of VTE in OC users was 3-fold higher (95% CI 1.3-6.8) than that in non-carriers. Carriers of FVL mutation taking OC showed an OR of 1.4 (95% CI 0.6-3.3), indicating a tendency to increase the risk of VTE. INTERPRETATION AND CONCLUSIONS: Because of the high prevalence of the PT20210A (6.5%) and FVL (2%) mutations in the general Spanish population and the increased risk of VTE associated with OC intake, genetic screening for these mutations should be considered in potential OC users belonging to families with thrombophilia.

Genetic regulation of plasma levels of vitamin K-dependent proteins involved in hematostatis: results from the GAIT Project. Genetic Analysis of Idiopathic Thrombophilia.

Vitamin K-dependent proteins play a critical role in hemostasis. We have analysed the genetic and environmental correlations between measures of several vitamin K-dependent proteins in 21 Spanish extended families, including 397 individuals. Plasma functional levels of factors II, VII, IX, X, protein C and functional protein S were assayed in an automated coagulometer. Antigenic levels of total and free protein S were measured using an ELISA method. A maximum likelihood-based covariance decomposition analysis was used to assess the heritability of each trait and the genetic and environmental correlations between all possible pairs. All of the plasma levels had a significant genetic component (heritability) ranging from 22% to 52% of the phenotypic variance. Among the 28 possible pairs of genetic correlations, 18 were significant at a level of p < 0.05 and six exhibited a p-value between 0.05 and 0.10. Positive environmental correlation was observed for 25 of the pairs (p < 0.05). We conclude that genetic effects account for a large proportion of the observed phenotypic variation in vitamin K-dependent proteins. Some of the genes appear to pleiotropically influence all of these traits, since most pairs of phenotypes exhibit significant genetic correlation. However, since these phenotypes show a high degree of environmental correlation, it is also likely that the same environmental factors influence them co-jointly.

Genetic susceptibility to thrombosis and its relationship to physiological risk factors: the GAIT study. Genetic Analysis of Idiopathic Thrombophilia.

Although there are a number of well-characterized genetic defects that lead to increased risk of thrombosis, little information is available on the relative importance of genetic factors in thrombosis risk in the general population. We performed a family-based study of the genetics of thrombosis in the Spanish population to assess the heritability of thrombosis and to identify the joint actions of genes on thrombosis risk and related quantitative hemostasis phenotypes. We examined 398 individuals in 21 extended pedigrees. Twelve pedigrees were ascertained through a proband with idiopathic thrombosis, and the remaining pedigrees were randomly ascertained. The heritability of thrombosis liability and the genetic correlations between thrombosis and each of the quantitative risk factors were estimated by means of a novel variance component method that used a multivariate threshold model. More than 60% of the variation in susceptibility to common thrombosis is attributable to genetic factors. Several quantitative risk factors exhibited significant genetic correlations with thrombosis, indicating that some of the genes that influence quantitative variation in these physiological correlates also influence the risk of thrombosis. Traits that exhibited significant genetic correlations with thrombosis included levels of several coagulation factors (factors VII, VIII, IX, XI, XII, and von Willebrand), tissue plasminogen activator, homocysteine, and the activated protein C ratio. This is the first study that quantifies the genetic component of susceptibility to common thrombosis. The high heritability of thrombosis risk and the significant genetic correlations between thrombosis and related risk factors suggest that the exploitation of correlated quantitative phenotypes will aid the search for susceptibility genes.

Functional effects of the ABO locus polymorphism on plasma levels of von Willebrand factor, factor VIII, and activated partial thromboplastin time.

Lower levels of factor VIII and von Willebrand factor (vWF) have been reported in individuals with blood type O compared with individuals with other ABO blood types. However, this relationship has been demonstrated only by association studies and not by linkage studies. Also, it is not clear whether the ABO locus exerts a functional effect directly on these plasma factors or whether the ABO locus is in linkage disequilibrium with another locus that controls these factors. To distinguish between these 2 possibilities, we applied new statistical methods combining linkage and association tests in a pedigree-based sample. In contrast to most previous studies that used the ABO phenotypes, our study used the ABO genotypes, permitting us to distinguish AO from AA and BO from BB. Our results clearly showed significant linkage between the ABO locus and vWF antigen (P=0.00075). In addition, factor VIII coagulant activity and activated partial thromboplastin time showed suggestive linkage with the ABO locus (P=0.10 and P=0.13). All 3 plasma phenotypes showed significant differences between OO and non-OO genotypes. In addition, vWF antigen exhibited significant differences between O heterozygotes and non-OO homozygotes. This study is unique because it used a combined linkage and association test, which indicated that the ABO locus itself has a functional effect on these plasma phenotypes.

Optimization of a simple and rapid single-strand conformation analysis for detection of mutations in the PROS1 gene: identification of seven novel mutations and three novel, apparently neutral, variants.

Anticoagulant protein S (PS) deficiency is a known risk factor for thrombophilia. The structure and high allelic heterogeneity of the PS gene (PROS1), together with the presence of a 97% homologous pseudogene, complicates PROS1 analysis. We have optimized a simple, fast, and non-isotopic Single-Strand Conformation Analysis (SSCA or SSCP) method for PROS1 mutation detection. This is accomplished through the analysis of the single-stranded and heteroduplex DNA fragments corresponding to 15 PCR segments that include part of the 5'-upstream region and the 15 PROS1 exons with their intron boundaries. To standardize the method, 13 known PROS1 mutations or allele variants in 10 different fragments were analyzed under different electrophoretic conditions. The results indicated that, using a combination of two different electrophoretic settings, all the allele variants could be detected as a single-strand band shift and/or by the presence of a heteroduplex. This method was used to analyze the PROS1 gene in 31 propositi with different types of PS deficiency and thrombosis. Ten different cosegregating mutations, seven of which are novel (143C->G, L-27H, G96X, M599T, P626L, 1418delA, and 1877delT), were identified in the five families suffering from type I or quantitative PS deficiency and in four of the nine families with coexistence of type I and type III phenotypes. No clearly co-segregating PROS1 mutations were identified in any of the 17 type III propositi analyzed, although eight of them were heterozygotes for the uncommon P460 allele of the S/P460 variant. Furthermore, five apparently neutral allelic variants, three of which are novel (-296C->T, 182G->C and T57S), were identified in a normal control, two type I/III and two type III PS-deficient pedigrees.

Genetic determinants of hemostasis phenotypes in Spanish families.

BACKGROUND: Recent studies have described genetic mutations that affect the risk of thrombosis as a result of abnormal levels of such hemostatic parameters as protein C, protein S, and the activated protein C resistance ratio. Although these mutations suggest that genes play a part in determining variability in some hemostasis-related phenotypes, the relative importance of genetic influences on these traits has not been evaluated. METHODS AND RESULTS: The relative contributions of genetic and environmental influences to a panel of hemostasis-related phenotypes were assessed in a sample of 397 individuals in 21 extended pedigrees. The effects of measured covariates (sex, age, smoking, and exogenous sex hormones), genes, and environmental variables shared by members of a household were quantified for 27 hemostasis-related measures. All of these phenotypes showed significant genetic contributions, with the majority of heritabilities ranging between 22% and 55% of the residual phenotypic variance after correction for covariate effects. Activated protein C resistance ratio, activated partial thromboplastin time, and Factor XII showed the strongest heritabilities, with 71.3%, 83.0%, and 67.3%, respectively, of the residual phenotypic variation attributable to genetic effects. CONCLUSIONS: These results clearly demonstrate the importance of genetic factors in determining variation in hemostasis-related phenotypes that are components of the coagulation and fibrinolysis pathways and that have been implicated in risk for thrombosis. The presence of such strong genetic effects suggests that it will be possible to localize previously unknown genes that influence quantitative variation in these hemostasis-related phenotypes that may contribute to risk for thrombosis.

Homozygotes for prothrombin gene 20210 A allele in a thrombophilic family without clinical manifestations of venous thromboembolism.

BACKGROUND AND OBJECTIVE: A new genetic risk factor for venous thromboembolism has recently been described which involves a G to A transition at position 20210 in the 3' untranslated region of the prothrombin gene. To date, only a few homozygotes for this mutation have been reported and in most of cases, they suffered from thrombotic disease. Here, we describe a pedigree including both heterozygous and homozygous subjects for prothrombin (PT) 20210 A. DESIGN AND METHODS: This family was recruited in 1996 as part of our GAIT (Genetic Analysis of Idiopathic Thrombophilia) project. To qualify for the GAIT study, a pedigree was required to have at least 10 living individuals in three or more generations (i.e. extended pedigree). The pedigrees were selected through probands with idiopathic thrombophilia. A complete set of plasma and DNA determinations related to hemostasis was performed on this family. RESULTS: The plasma studies yielded normal results in all of the individuals. The family members who had a history of thromboembolism were heterozygous carriers of the PT 20210 A variant. In addition, 4 relatives who were heterozygous, and two who were homozygous for this A allele, failed to show clinical manifestations. These two homozygotes were 51 and 19 years old. INTERPRETATION AND CONCLUSIONS: This case exemplifies the complexity of thrombotic disease since individuals homozygous for a mutant gene do not exhibit symptoms while heterozygous individuals often do exhibit the disease. This case suggests that the new genetic risk factor for thrombosis (i.e. PT 20210 A) may not be as strong as most of the previously described genetic risk factors.