FV G1691A Mutation Research Articles

Role of Genetic Thrombophilia Markers in Thrombosis Events in Elderly Patients with COVID-19

Thrombosis is an extremely dangerous complication in elderly patients with COVID-19. Since the first months of the pandemic, anticoagulants have been mandatory in treatment protocols for patients with COVID-19, unless there are serious contraindications. We set out to discover if genetic thrombophilia factors continue to play a triggering role in the occurrence of thrombosis in patients with COVID-19 with prophylactic or therapeutic anticoagulants. We considered the following genetic markers as risk factors for thrombophilia: G1691A in the FV gene, C677T and A1298C in the MTHFR gene, G20210A and C494T in the FII gene, and (-675) 4G/5G in the PAI-I gene. In a cohort of 176 patients, we did not obtain a reliable result indicating a higher risk of thrombotic complications when taking therapeutic doses of anticoagulants in carriers of genetic markers for thrombophilia except the C494T mutation in the FII gene. However, there was still a pronounced tendency to a higher incidence of thrombosis in patients with markers of hereditary thrombophilia, such as FV G1691A and FII G20210A mutations. The presence of the C494T (Thr165Met) allele in the FII gene in this group of patients showed a statistically significant effect of the mutation on the risk of thrombotic complications despite anticoagulant therapy.

Оценка протромботического фенотипа у асимптомных носителей мутации G1691A в гене фактора V и/или мутации G20210A в гене протромбина с помощью теста генерации тромбина

Введение. К числу безусловных наследственных детерминант тромбофилии относятся мутации в генах факторов II (G20210A) и V (G1691A). Однако их наличие, особенно в гетерозиготной форме, не всегда приводит к развитию тромботических осложнений, что свидетельствует о целесообразности поиска новых объективных методов выявления протромботического фенотипа у носителей рассматриваемых мутаций. Тест генерации тромбина (ТГТ) отражает состояние гемостаза индивидуума в совокупности взаимодействия прокоагулянтных и антикоагулянтных механизмов и позволяет эффективно выявлять гиперкоагуляцию. Цель исследования: установить целесообразность использования ТГТ для оценки гемостатического потенциала у асимптомных носителей мутаций в генах фактора V (G1691A) и/или протромбина (G20210A). Материалы и методы. Обследовано 42 асимптомных носителя мутации FV G1691A и/или FII G20210A (14 мужчин и 28 женщин, средний возраст — 37,0 ± 15,0 лет). Постановка ТГТ выполнялась в бедной тромбоцитами плазме. В тромбинограмме оценивали следующие показатели: PT (Peak thrombin — максимальное количество тромбина, образующегося в образце), ETP (endogenous thrombin potential — эндогенный тромбиновый потенциал), Lag-time — время инициации свёртывания и V (скорость образования тромбина). Результаты. Согласно полученным данным, гетерозиготное носительство мутаций FV G1691A и/или FII G20210A может ассоциироваться как с протромботическим, так и с нормальным фенотипом. У асимптомных носителей Лейденской мутации повышенные значения ЕТР и РТ обнаружены в 44% случаев, в то время как резистентность к активированному протеину С — в 67%. У большей части носителей мутации в гене протромбина отмечены превышающие норму значения ЕТР и РТ (71% и 57% случаев, соответственно). Скорость генерации тромбина превышала нормальные величины у 57% носителей мутации FV G1691A и у 64% носителей мутации FII G20210A. Значительную часть обследованных можно охарактеризовать как имеющих промежуточный протромботический фенотип, учитывая наличие у них одновременно как нормальных, так и патологических показателей ТГТ. Заключение. ТГТ является перспективным методом в плане создания индивидуального профиля риска для асимптомных носителей мутаций, ассоциированных с наследственной тромбофилией. Introduction. Mutations in genes of factors II (G20210A) and V (G1691A) are well known determinants of hereditary thrombophilia, but their presence, especially in the heterozygous form, does not always lead to the development of thrombotic complications.This indicates the importance of objective methods for the detection of prothrombotic phenotype in carriers of these mutations. Thrombin generation test (TGT) demonstrates the state of individual’s hemostasis in the interaction of procoagulant and anticoagulant mechanisms and allows to detect the hypercoagulability. Aim: to assess the hemostatic potential in asymptomatic carriers of FV G1691A or/and FII G20210A mutations by TGT. Materials and methods. We examined 42 asymptomatic carriers of FV G1691A mutation and/or G20210A prothrombin gene mutation (14 men and 28 women, average age — 37,0 ± 15,0 years). TGT was performed in platelet-poor plasma. In thrombinogram we assessed following parameters: PT (Peak thrombin is the maximum amount of thrombin formed in the sample), ETP (endogenous thrombin potential), Lag-time (coagulation initiation time) and V (thrombin generation rate). Results. According to data obtained, heterozygous carriage of FV G1691A and/or FII G20210A mutations can be associated with both prothrombotic and normal phenotypes. In asymptomatic carriers of Leiden mutation we revealed elevated values of ETP and RT in 44% of cases, while resistance to activated protein C — in 67%. The majority of FII G20210A mutation carriers demonstrated increased values of ETP and PT (71% and 57%, respectively). Thrombin generation rate exceeded normal values in 57% and 64% carriers of FV G1691A and FII G20210A mutations, respectively. The majority of examined patients can be characterized as having intermediate prothrombotic phenotype, taking into account that they had both normal and pathological values of TGT parameters. Conclusion. TGT is a perspective method for creating an individual risk profi le in asymptomatic carriers of mutations associatedwith hereditary thrombophilia.

Primary Budd–Chiari syndrome in a 3-year-old boy with homozygous factor V Leiden G1691A mutation

Budd-Chiari syndrome (BCS) is an uncommon disorder characterized by obstruction of hepatic venous outflow. The primary BCS is a rare disease with an incidence about 0.2 per million inhabitants per year. We present a 3-year-old boy with intrahepatic inferior vena cava clot. Because of decreased levels of protein C (38.7 %), F II (69.1 %), and activated protein C resistance (1.43), a mutational gene analysis was performed. The patient was found to be homozygous for the FV G1691A mutation. The primary BCS is a rare disease especially in childhood. Activated protein C resistance caused by the factor V Leiden mutation may be responsible for primary BCS. Prompt recognition of underlying prothrombotic disease and early initiation of their specific therapy might translate into rapid improvement of liver disease.

The frequency of FV G1691A and PT G20210A mutations in an Albanian population.

The frequency of FV G1691A and PT G20210A mutations in an Albanian population.

Genetic Mutations in Turkish Population With Pulmonary Embolism and Deep Venous Thrombosis

Venous thromboembolism (VTE) is a universal health hazard. Inherited and acquired risk factors increase the risk of VTE. We evaluated the relationship between factor V (G1691A, A1090G, and A1299G), prothrombin (PT G20210A), methylenetetrahydrofolate reductase (MTHFR C677T) mutations, plasminogen activator inhibitor 1 (PAI-1 -675) polymorphism, and VTE in Turkish population. In all, 80 patients with VTE and 104 controls were included. Heterozygous factor V Leiden (FVL) mutation was significantly higher among patients (P = .04) with allele frequency of 6.3% (P = .01). Heterozygous PT G20210A mutation was also significantly higher among patients (P = .001) with allele frequency of 6.9% (P = .003). MTHFR 677TT genotype was significantly higher in patients (P = .009) with allele frequency of 23.8% (P = .005). No significant difference was found in FV A1090G and FV A1299G mutation rate as well as PAI-1 genotypes and their allele frequencies (P > .05). Thus, frequencies of FV G1691A, PT G20210A, and MTHFR C677T mutations are higher in patients with VTE. FV A1090G, FV A1299G mutations, and PAI-1 gene polymorphisms may not be a risk factor for VTE in Turkish population.

Anti-prothrombin antibodies are associated with thrombosis in children

Introduction This investigation aimed to evaluate thrombotic risk factors in children, with special reference to autoantibodies against prothrombin and protein S. Materials and methods We studied 57 consecutive Swedish children and adolescents referred with a radiologically confirmed acute thrombotic event. Clinical data were collected and a thrombophilia investigation was performed, including analysis of autoantibodies against protein S (anti-PS) and prothrombin (anti-PT). The anti-PS and anti-PT autoantibodies were also investigated in sera from 47 healthy controls. Detection of autoantibodies was performed by quantitative enzyme-linked immunosorbent assays. Results Results for anti-PT antibodies were positive in 21% (12/57) of the patients and 2.1% (1/47) of the controls (OR 12.0, 95% CI 1.7–534; p = 0.005). Seven percent (4/57) of the patients and 2.1% (1/47) of the controls were positive for anti-PS antibodies (OR 3.4, 95% CI 0.3–174; p > 0.30). The FV G1691A mutation was found in 25% (14/57), and 44% (25/57) had 2 or more prothrombotic risk factors. Sixty percent (34/57) of the thrombosis patients were female. Peaks in frequency of thromboembolic events were found in the neonatal and the adolescent periods. Fifty-three percent (30/57) had thrombosis in the lower venous system. Associated clinical conditions occurred in 91% (52/57) : systemic illness in 31% (18/57), infections in 26% (15/57), and oral contraceptive use in 25% (14/57). Four percent (2/57) had no apparent clinical or prothrombotic risk factors. Conclusions This study suggests that anti-PT autoantibodies may be common risk factors for thrombosis in children, and it confirms the multifactorial nature of pediatric thrombosis.

Association of the protein Z ATG haplotype with symptomatic nonvascular stroke or thromboembolism in white children: a family-based cohort study

AbstractTo clarify the role of protein Z (PZ) in children with stroke/thromboembolism (TE), the present haplotype (HT)–based family study was performed. We genotyped 365 pediatric stroke/TE families (stroke n = 216; TE n = 149) for 4 single nucleotide polymorphisms (SNPs; rs3024718, rs3024731, rs3024772, and rs3024778) to assess the association between genetic variation within a conserved block of linkage disequilibrium harboring the PZ gene and pediatric TE. Association was assessed with use of the transmission disequilibrium test (TDT), corrected for multiple testing (permutation testing: HAPLOVIEW). In addition, PZ antigen was determined and correlated with carriership of PZ haplotypes and the FV G1691A mutation. Rs3024718, rs3024731, and rs3024772 are in tight linkage disequilibrium (LD) and define 4 haplotypes, capturing 97% of the genetic variation for this LD block. HT1 (ATG) was significantly overtransmitted from parents to affected offspring (HT frequency 73.5%, T:U 122:80, χ2 = 8.791, P = .003). The ATG risk haplotype was significantly correlated with greater PZ antigen levels. Multivariate analysis adjusted for age, sex, established thrombophilias, smoking, fibrinogen, and PZ levels revealed a significant association of the ATG haplotype and TE in children (odds ratio [OR] 1.4; 95% confidence interval [95% CI] 1.08-1.93). Our results suggest that the ATG haplotype of the PZ gene is a genetic marker for symptomatic TE in white German children.

Do common prothrombotic mutations influence the risk of cerebral ischaemia in patients with patent foramen ovale?

Conflicting results are available on the association of prothrombotic genetic abnormalities with patent foramen ovale (PFO)-related cerebral ischaemia. We comprehensively sought and identified studies of the association of both the factor V Leiden (FV(G1691A) mutation) and the prothrombin mutation (PT(G20210A) mutation) with PFO-related cerebral ischaemia and did meta-analyses to assess the evidence for such a relation. We analysed data from six eligible studies in 856 cases and 1,001 control subjects. Additional unpublished data from a new series including 463 subjects were also entered into the analysis. The PT(G20210A) variant was significantly associated with PFO-related stroke in comparison with both control subjects (odds ratio [OR] 3.85; 95% confidence interval [CI] 2.22 to 6.66) and non-PFO-associated stroke patients (OR 2.31; 95% CI 1.20 to 4.43), whereas a trend toward an association was observed for the FV(G1691A) mutation (OR 1.18; 95% CI 0.73 to 1.90, compared to control subjects; OR 1.14; 95% CI 0.62 to 2.09, compared to non-PFO-associated stroke patients). The status of carrier of either the FV(G1691A) mutation or the PT(G20210A) variant was associated with a risk for stroke of 1.98 (95% CI 1.38 to 2.83) and 1.62 (95% CI 1.03 to 2.57), as compared to control subjects and non-PFO-associated stroke patients, respectively. Addition of common prothrombotic genetic variants to standard initial screening may contribute to stratifying PFO-associated stroke patients at different risk of ischaemic events and targeting secondary prevention strategies.

Influence of the factor II G20210A variant or the factor V G1691A mutation on symptomatic recurrent venous thromboembolism in children: an international multicenter cohort study.

To determine the relative importance of the factor (F) II G20210A or FV G1691A mutations as risk factors or predictors for fatal/non-fatal recurrent venous thromboembolism (VTE) in children. In the present cohort, the rate of VTE recurrence and the time to recurrence in relation to FII, FV, age, and sex was determined in consecutively enrolled patients with VTE aged newborn to <or=18 years carrying the FII (n = 64) or FV (n = 194) mutation. 158 children with VTE without thrombophilia served as controls. Patients were followed for a median of 58 months. Data were pooled across participating sites to increase power and to enhance the generalizability of the data. Incidence rates were given as events per 1000 person-years. Of the 416 children enrolled, 44 had recurrent VTE at a median of 12 months following VTE onset. The overall incidence rate of recurrence was 19.8, 57.9 in patients with the FII variant, 17.9 for FV carriers, and 11.8 in the control cohort. When comparing FII patients, FV children and the control cohort multivariate analysis (Cox regression) adjusted for age and sex showed that the FII variant (hazard ratio 2.6; 95% confidence interval 1.1-5.9) influenced the hazard for recurrent VTE. Based on multivariate analysis, the presence of the FII variant was associated with an increased risk of VTE recurrence.

Evaluation of Inherited Prothrombotic Risk Factors in Children with Acute Lymphoblastic Leukemia.

This retrospective study was designed to determine the prevalence of inherited prothrombotic risk factors (Factor V Leiden (FV) G1691A and prothrombin G20210A mutations, TT677 genotype of the methylenetetrahydrofolate reductase (MTHFR), protein C, protein S, antithrombin deficiencies) in a population of children with ALL treated according to the FRALLE 2000 study Protocol (High Risk and Standard Risk groups). The study was performed in 5 French Centers including Amiens, Angers, Paris Trousseau, Rouen and Saint-Etienne. From December 2000 to March 2006, 354 children aged 1 to 18 years old were consecutively admitted for ALL and were enrolled in the FRALLE 2000 Protocol. Among them, 281 patients were investigated for hereditary prothrombotic defects at the time of ALL diagnosis. Informed parental consent was required for gene analysis. Abnormal test results for protein S (functional activity and free protein S antigen concentration), protein C and antithrombin were controlled on a second blood sample after induction. In the population studied, the prevalence of one established prothrombotic risk factor was 19,2%: the FV G1691A mutation was diagnosed in 10 patients (3.6%), all heterozygous, 10 patients (3.6%) showed the heterozygous prothrombin G20210A mutation, the TT677 MTHFR genotype was found in 34 children (12.7%), 1 patient showed protein C deficiency (0.4%). No antithrombin deficiency was detected. The prevalence of inherited protein S deficiency could not be evaluated because of missing data in the family medical history. Combined prothrombotic defects were found in 2 patients (0.71%): heterozygous FV G1691A mutation combined with heterozygous prothrombin G20210A mutation in 1 patient and combined with TT677 MTHFR genotype in the second patient. Except for TT677 MTHFR genotype, the prevalence of hereditary prothrombotic risk factors in children with ALL in France were found within the prevalence reported for children treated for ALL (table 1) and comparable to the prevalence in healthy Europeans (Junker et al. 1999, Margaglione et al 2001, Mueller et al. 2005).Comparison of the prevalence of inherited prothrombotic risk factors in children with ALLCountryPopulationFV G1691A +/− ++PT G20210A +/− +/+MTHFR TT677ATPCNowakGöttl et al 1999 (n=301)GermanyALL children5.3% 0.3%2% 0%7.7%0.7%2.3%Mauz-Körholz et al. 2000 (n=108)GermanyALL children5.6% 0%2.8% 0%5.6%0%2.7%Mitchell et al. 2002 (n=60)CanadaALL children3.3% 0%2% 0%NENENEPresent study (n=281)FranceALL children3.6% 0% (n=277)3.6% 0%(n=279)2.7% (n=268)0%0.4%AT: antithrombin deficiency ; PC: protein C deficiency ; NE : non evaluated

Prothrombotic risk factors in patients with recurrent thrombosis of the arteriovenous fistula

Background. Arteriovenous (AV) fistula thrombosis is a common and expensive complication. In this study, we aimed to investigate the role of prothrombotic risk factors in the development of recurrent AV fistula thrombosis. PatientsandMethods. We evaluated 11 patients with chronic renal failure and recurrent thrombosis of their AV fistula who were referred to the Hacettepe University Faculty of Medicine Pediatric Hematology Unit between January 1998 and June 2005 for prothrombotic risk factors. Results. Of the 11 patients, 6 were children (mean age, 14.8 � 2.6 years), and 5 were adults (mean age, 37.6 � 16.6 years). All patients had had at least 2 episodes of thrombosis in their AV fistula, with an overall total of 31 episodes (mean: 2.8 � 1.3 episodes, range: 2–6 episodes). Eight of the 11 patients (72.7%) had at least one prothrombotic risk factor. Two patients (18.2%) had FV G1691A mutations, and two (18.2%) had prothrombin G20210A mutations. These mutations are more common in patients with recurrent AV fistula thrombosis than in a healthy Turkish population (18.2% versus 7.1% for the FV G1691A mutation and 18.2% versus 2.2% for the prothrombin G20210A mutation; p < 0.05). Conclusion. Recurrent AV fistula thrombosis should be considered as important as other types of recurrent thrombosis, and hereditary prothrombotic risk factors should be investigated to detect patients who have a thrombotic tendency in countries where these hereditary risk factors are common.

Evaluation of Thrombotic Events in Haemophiliacs Undergoing Major Orthopaedic Surgery without Thrombosis Prophylaxis.

Introduction:Major orthopaedic procedures and the presence of thrombophilia are risk factors of thrombotic events. In patients with haemophilia undergoing hip or knee replacement the importance of thrombosis prophylaxis with heparin in the postoperative period is still unknown. The aim of the present study was to evaluate the occurence of thrombotic events in haemophiliacs undergoing major surgery without thrombosis prophylaxis.Patients: A total of 32 pts with haemophilia A (severe:27 pts, moderate:4 pts, mild:1pt; median age:47yrs, range:27–73yrs) undergoing hip (n=9)or knee (n=35) replacement were analysed in our haemophilia treatment center. Pts with inhibitors were excluded. Surgical interventions were performed using recombinant (n=37) or plasma-derived (n=7) FVIII for 12 to 15 postoperative days. The median initial dose of FVIII was 82 IU/Kg−1, followed by median FVIII doses of 54 IU/kg−1over the first four days. All pts received thrombosis prophylaxis with graduated compression stockings only. In addition to factor VIII activity, APC resistance, FV G1691A mutation and the FII G20210A variant (FII) were investigated.Results: No thrombotic events in the postoperative period was dokumented. The median FVIII activity was 153% (range:85–347%), the Body mass index (BMI:kg/m2) was 23.1(range:18.2–30.5). During the first four postoperative days FVIII levels >150% were measured in 24/44 (55%) operative procedures. BMI>25 were shown in 12/32 (38%) pts, and age >40yrs was documented in 23/32 (72%) pts. In 1/30 (3%) pt APC resistance and none of our pts FII were identified.Conclusion: In our study group elevated FVIII levels and additional risk factors (BMI>25, age>40years) seems not to influence relevantly the occurrence of thrombotic events in pts with haemophilia undergoing hip or knee replacement without thrombosis prophylaxis. Further studies are required to confirm whether a thrombosis prophylaxis with heparin is needed in haemophiliacs undergoing high risk surgery.

Relevance of Thrombophilic Risk Factors on Clinical Phenotype in Patients with Haemophilia A.

Introduction: By assuming the hypothesis, that a high coinheritance of genetic haemostatic abnormalities influences the clinical phenotype in patients with coagulation disorders, we analysed the bleeding tendency in adult patients with haemophilia A.Patients: A total of 49 patients with haemophilia A (severe:20 patients, moderate:12 patients, mild:17 patients; median age:44 years, range:22–78 years) and 80 sex-matched healthy subjects (median age:26 years, range:16–58 years) were studied in our haemophilia treatment center. Two of this patients have an inhibitor against factor VIII. 10 of 49 patients receive the factor VIII replacement therapy on demand. In addition to factor VIII activity, FV G1691A mutation and the FII G20210A variant were investigated.Results: In our study the prevalence of FV G1691A was significantly higher among patients 6/49 (severe:5, moderate:1) than among control subjects 2/80 [12% vs 2.5%; p=0.03 OR 4.9]. We found no differences in the FII G20210A variant in 2/49 patient (moderate:1, mild:1) as compared to 2/80 among controls [4% vs 2.5%; p=0.62 OR 1.63 ]. In none of our patients both defects together were identified.Within the last year the onset of bleeding was not different in thrombophilic haemophilia patients (n=8) 64 bleeding episodes/year compared with non-carriers (n=41) 284 bleeding episodes/year [8 vs 7 bleeding episodes/year/patient; p=0.72; OR 1.15].Conclusion: The FV G1691A was found significantly more frequent in the thrombophilic haemophiliacs than in the general population. In our smal study group we could not demonstrate a relevant influence of the FV G1691A and FII G20210A on bleeding tendency. Further studies are needed to confirm whether FV G1691A and FII G20210A plays a role on the influence of bleeding tendency in haemophilia A patients.

Symptomatic thrombosis in Turkish neonates.

To investigate the association of two common prothrombotic mutations, factor V G1691A (FV G1691A) and prothrombin G20210A (PT G20210A), in neonates with thrombosis. Twenty-six neonates with thrombosis were assessed with the spectrum of assays for thrombophilia, including the two DNA-based prothrombotic factors. Eight patients (31%) had the FV G1691A mutation in heterozygous state. PT G20210A mutation was detected in four patients (15%). Overall, two common prothrombotic factors were detected in 12 neonates (46%) and an underlying disease or a triggering event in 18 neonates (69%). Thrombosis was considered to be idiopathic in five neonates (19%). The pathogenesis of thrombosis in neonates is multi-factorial. Along with underlying diseases or triggering events, congenital prothrombotic factors (FV G1691A and PT G20210A) showed a trend toward a higher frequency in neonates with thrombosis. These data indicate that mutations associated with underlying disorders in neonates may contribute to the development of thromboembolic disease.

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Recurrent Pregnancy Loss and Its Relation to FV Leiden, FII G20210A and Polymorphisms of Plasminogen Activator and Plasminogen Activator Inhibitor

Thrombophilic disorders and hypofibrinolysis were demonstrated to be risk factors in a majority of women with recurrent pregnancy loss (RPL) and infertility. We investigated the association of FV G1691A mutation, F II G20210A gene polymorphism (PM), 4G/5G PAI-1 and Alu I/D tPA PM in 32 women with infertility and 49 women with at least 2 unexplained early abortions. FV Leiden mutation was significantly more common in women with RPL (10%, p = 0.02) and infertility (19%, p = 0.0005) compared with controls (2%). PAI-1 4G PM and t-PA Alu I PM, alone or in combination, were not associated with RPL or infertility. 9/49 women with RPL showed coagulation disorders with heterozygous FV Leiden mutation (5), FXII (1), protein C (1) or protein S (2) deficiency. However, due to the small number of patients studied, no definite conclusion can be drawn.

Outcome of kidney transplantation in patients with inherited thrombophilia: data of a prospective study.

Inherited prothrombotic risk factors predispose patients to thromboembolic events. In kidney transplant recipients, thrombophilia may manifest itself with venous thrombosis, microvascular occlusion, or acute rejection with major consequences for allograft survival. This is a prospective study on 165 renal allograft recipients to evaluate the contribution of genetic thrombophilic risk factors to transplant outcome. Besides antithrombin, protein C, and protein S deficiencies, none of which was found in our patient group, factor V G1691A (FV G1691A), prothrombin G20210A (PT G20210A) mutations, and methylenetetrahydrofolate reductase (MTHFR) gene C677T polymorphisms were studied. The primary endpoint of the study was occurrence of an acute rejection within the first 90 d and transplant loss within 1 yr. Heterozygous FV G1691A and PT G20210A mutations and the MTHFR T677T variant were significantly associated with acute rejections with rejection rates of 68%, 67%, and 71%, respectively, as compared with 35% in patients not carrying these genotypes. Many rejections that were histologically proven were acute vascular ones. Transplant loss was significantly associated exclusively with the PT G20210A group (50% 1-yr graft survival; odds ratio, 10.0; 95% confidence interval, 1.8 to 56.1). PT G20210A patients exerted the highest prothrombotic activity pretransplant, as determined by prothrombin 1.2 fragments (PT F1.2), which may be the background for minor outcome. In conclusion, common prothrombotic mutations are significantly associated with acute rejections, especially vascular rejections, and for PT G20210A also with early transplant failure. Screening for hypercoagulable states pretransplant is recommended to intensify anticoagulatory treatment posttransplant.

Increased lipoprotein (a) levels as an independent risk factor for venous thromboembolism

Elevation of serum lipoprotein (a) (Lp[a]) is a known risk factor predisposing to cardiovascular and cerebrovascular disease. However, little is known about the role of increased Lp(a) in venous thromboembolism (VTE). This study evaluated the role of Lp(a) among a panel of established hereditary thrombogenic defects in patients with VTE. A total of 685 consecutive patients with at least one episode of VTE and 266 sex- and age-matched healthy controls were screened with regard to activated protein C resistance, protein C, protein S, and antithrombin deficiency, elevated serum levels of Lp(a), and the factor V G1691A, MTHFR C677T, and prothrombin G20210A mutations. Elevated Lp(a) levels above 30 mg/dL were found in 20% of all patients, as compared to 7% among healthy controls (P &lt; .001, odds ratio [OR] 3.2, 95% confidence interval [CI], 1.9-5.3). The coexistence of FV G1691A and elevated Lp(a) was significantly more prevalent among patients with VTE than in the control group (7% versus 0.8%; P &lt; .001, OR 9.8, 95% CI, 2.4-40.7). No other established prothrombotic risk factor was found to be significantly combined with increased Lp(a). These data suggest that Lp(a) concentrations greater than 30 mg/dL are a frequent and independent risk factor for VTE. Furthermore, elevated Lp(a) levels might contribute to the penetrance of thromboembolic disease in subjects being affected by other prothrombotic defects, such as FV G1691A mutation.

Increased lipoprotein (a) levels as an independent risk factor for venous thromboembolism

AbstractElevation of serum lipoprotein (a) (Lp[a]) is a known risk factor predisposing to cardiovascular and cerebrovascular disease. However, little is known about the role of increased Lp(a) in venous thromboembolism (VTE). This study evaluated the role of Lp(a) among a panel of established hereditary thrombogenic defects in patients with VTE. A total of 685 consecutive patients with at least one episode of VTE and 266 sex- and age-matched healthy controls were screened with regard to activated protein C resistance, protein C, protein S, and antithrombin deficiency, elevated serum levels of Lp(a), and the factor V G1691A, MTHFR C677T, and prothrombin G20210A mutations. Elevated Lp(a) levels above 30 mg/dL were found in 20% of all patients, as compared to 7% among healthy controls (P < .001, odds ratio [OR] 3.2, 95% confidence interval [CI], 1.9-5.3). The coexistence of FV G1691A and elevated Lp(a) was significantly more prevalent among patients with VTE than in the control group (7% versus 0.8%; P < .001, OR 9.8, 95% CI, 2.4-40.7). No other established prothrombotic risk factor was found to be significantly combined with increased Lp(a). These data suggest that Lp(a) concentrations greater than 30 mg/dL are a frequent and independent risk factor for VTE. Furthermore, elevated Lp(a) levels might contribute to the penetrance of thromboembolic disease in subjects being affected by other prothrombotic defects, such as FV G1691A mutation.

Role of genetic prothrombotic risk factors in childhood caval vein thrombosis.

Childhood caval vein thrombosis has a high incidence especially in the first year of life. Besides deficiencies of protein C, protein S, antithrombin and plasminogen, the factor (F) V G1691A mutation, the prothrombin (PT) G20210A variant, the methylenetetrahydro-folate reductase (MTHFR) TT677 genotype, or increased lipoprotein (Lp) (a) > 30 mg/dl have emerged as important prothrombotic risk factors in childhood vascular accidents. 27 consecutive childhood patients with inferior caval vein thrombosis and 100 healthy age-matched controls were investigated for the presence of these prothrombotic risk factors with respect to the first thrombotic onset. In 19 out of 27, patients thrombosis occurred during infancy; the remaining vascular accidents were diagnosed during puberty. In 13 out of the 19 infants, vascular occlusion occurred spontaneously, five times associated with renal venous thrombosis. 68.4% of patients in the first year of life (n = 13) showed at least one prothrombotic risk factor. The FV mutation (heterozygous n = 4, homozygous n = 1). Lp (a) > 30 mg/dl and kringle 4 repeats < 28 (n = 4), MTH FR TT677 with mild hyperhomocysteinaemia (> 95th age-dependent percentile, i.e. 8.5 micromol/l: n = 3) and antithrombin deficiency type II (n = 1) were diagnosed with an overall odds ratio/95% confidence interval of 9.2/3.1-27.4. In the adolescent group, genetic risk factors were found in 50% of patients investigated (FV mutation (n = 1), PT variant (n = 3); odds ratio/95% confidence interval: 4.2/0.97-18.6). Data presented here suggest that genetic prothrombotic risk factors play an important role in childhood caval vein thrombosis. Remarkably, during puberty and adolescence the predominant defect diagnosed was the PT G20210A variant, whereas the FV G1691A mutation had a higher incidence during infancy.