Coexistence of factor V Leiden and Factor II A20210 mutations and recurrent venous thromboembolism

Patients carrying the FV Leiden or the FII A20210 mutation have a high risk of venous thromboembolism. Among 542 patients with a documented diagnosis of deep venous thrombosis in one leg consecutively referred for a thrombophilic work-up, we have retrospectively assessed the rate of objectively documented previous recurrence in carriers of both FV Leiden and FII A20210 mutations. Eighty-two patients had experienced 115 episodes of recurrent venous thromboembolism. The rate of recurrent venous thromboembolism was 29.2% among subjects with and 14.5% in those without deficiencies of natural anticoagulant proteins (p = 0.055), and 24.6% among patients with and 14.0% in those without antiphospholipid antibodies (p = 0.036). The frequency of having a recurrent thromboembolism was 16.2%, 20.0%, and 36.4% among carriers of FV Leiden, FII A20210 mutation, or both gene defects, respectively, and 12.8% in subjects carrying neither mutation (p for trend = 0.004). When adjusted for age, sex, and thrombophilic risk factors, the rate was higher among patients with than in those without deficiencies of natural anticoagulant proteins (OR: 3.0; 95% CI: 1.2-7.5), aPL 2.5 (95% CI: 1.3-4.9), or both FV Leiden and FII A20210 gene mutations (OR 4.8; 95% CI: 1.9-12.2). The rate of previous recurrent venous thromboembolism was significantly higher in subjects carrying both FV Leiden and FII 20210 mutations and was comparable to that observed in subjects with deficiencies of natural anticoagulant proteins or antiphospholipid antibodies.     

Thrombophilic risk factors and homocysteine levels in Behçet's disease in eastern Spain and their association with thrombotic events

Beh?et's disease (BD) is a chronic inflammatory disorder in which thrombosis occurs in about 30% of patients. The prothrombotic mechanisms are unknown. Thrombophilic defects and hyperhomocysteinaemia may be involved in the pathogenesis of thrombotic events, although results have been controversial. Moreover, no information is available on this issue for eastern Spain. We studied the prevalence of inherited and acquired thrombophilic risk factors in 79 patients with BD (43 men, 36 women) who had (n = 23) or did not have (n = 56) thrombosis, and in 84 healthy control subjects (42 men, 42 women). Risk factors examined were antithrombin, protein C and protein S levels, factor V Leiden, the prothrombin G20210A mutation, the methylenetetrahydrofolate reductase C677T polymorphism, and acquired thrombophilic risk factors, including anticardiolipin antibodies, lupus anticoagulant, and serum homocysteine levels. There were no differences between patients and controls in any of the parameters studied. When we studied BD patients with and without thrombotic events, the only thrombophilic defect that differed was the prothrombin G20210A mutation: Three out of 23 patients with thrombosis were carriers, compared with none of 56 patients without thrombosis (p = 0.022). Two of the three carriers developed catastrophic or recurrent thrombotic episodes; one was a homozygous carrier of the G20210A prothrombin mutation and the other was doubly heterozygous for the G20210A prothrombin mutation and factor V Leiden. A meta-analysis demonstrated an association of factor V Leiden and prothrombin mutation with thrombosis in BD. When studies from Turkey were excluded from the meta-analysis, only the prothrombin G20210A mutation was associated with thrombosis.     

Thrombophilic polymorphisms – factor V Leiden G1691A,prothrombin G20210A and MTHFR C677T – in Tunisian patients with cerebral venous thrombosis

Cerebral venous thrombosis (CVT) has been associated with thrombophilic defects. We performed a study to evaluate the role of three single nucleotide polymorphisms (SNP), factor V Leiden G1691A (FVL), prothrombin gene mutation G20210A (FII-G20210A) and methylenotetrahydrofolate reductase variant C677T (MTHFR-C677T), as risk factors for CVT in Tunisian patients. A single center case-control study (26 patients with CVT and 197 controls) was performed. Genomic DNA was tested for the three SNP. The principle finding was the association between FVL and CVT (p < 0.001, Odds ratio = 6.1, 95% confidence interval = 2.3–16.5). However, neither the FII-G20210 (p = 0.536) nor the homozygous MTHFR-C677T genotype (p = 0.325) variant contributed to the risk of CVT in these Tunisian patients.     

Inherited thrombophilia and first venous thromboembolism during pregnancy and puerperium

Venous thromboembolism is a rare but threatening complication of pregnancy. Little conclusive information is available on the actual risk of venous thromboembolism during pregnancy or puerperium in women with inherited thrombophilia, particularly in carriers of factor V Leiden and of the G20210A prothrombin gene mutation. To determine the pregnancy-related and puerperium-related risk of venous thromboembolism in women with inherited thrombophilia, we performed a case-control study on 119 women who had a first episode of deep vein thrombosis and/or pulmonary embolism during pregnancy or puerperium and 232 healthy women who had at least one pregnancy without thrombosis. Inherited thrombophilia was diagnosed in 47 patients (39.5%) and 15 controls (6.5%). The relative risk of venous thromboembolism was 10.6 (95% CI, 5.6-20.4) for heterozygous carriers of factor V Leiden, 2.9 (95% CI, 1.0-8.6) for heterozygous carriers of the prothrombin mutation and 13.1 (95% CI, 5.0-34.2) for those with antithrombin, protein C or protein S deficiency taken together. Sixty-eight of the 119 women (57%) had thrombosis after delivery, confirming the puerperium as a particularly high-risk period. When women were divided into two groups of those with antenatal or postnatal thrombosis. the relative risks associated with each type of inherited thrombophilia were of similar magnitude. In conclusion, women with inherited thrombophilia have an increased risk of venous thromboembolism during pregnancy. Among thrombophilic abnormalities, the prothrombin mutation was the weakest risk factor. Thrombosis occurred more frequently in puerperium than in pregnancy, whether or not thrombophilia was diagnosed.     

Molecular analysis of thrombophilic risk factors in patients with dural arteriovenous fistulas

Dural arteriovenous fistulas (DAVFs) are direct artery-to-cerebral venous sinus shunts. Our recent finding of a significantly increased prevalence of factor V (FV) Leiden in patients with DAVFs prompted us to evaluate prothrombinG20210A, MTHFRC677T, β-fibrinogenG455A, PAI-14G/5G and FXIIIVal34Leu as additional risk factors for thrombophilia in 26 patients with DAVFs and a group of age- and gender-matched controls. There was no significantly increased prevalence of these risk factors in DAVF patients. We conclude that FV Leiden is of pathogenetic significance in the aetiology of a subgroup of DAVFs whereas the other thrombophilic risk factors are not likely to be involved. Received: 15 July 2001, Received in revised form: 16 October 2001, Accepted: 23 October 2001     

Thromboelastography in patients with cerebral venous thrombosis

IntroductionCerebral venous thrombosis (CVT) is a rare presentation of venous thrombosis and has been associated with many conditions. In about 20% no risk factor is identified. The aim of this study was to assess the clot formation by thromboelastography (TEG) in patients with a history of CVT compared with healthy controls.Materials and MethodsTEG analysis was performed on recalcified blood samples of 19 CVT patients from a single centre cohort and 1:1 sex/ age (± 3 year) matched controls. Four TEG parameters were monitored: reaction time (r) to clot initiation, time to reach a 20 mm level of clot formation (K), slope angle alpha from r to K (α) and maximum vertical amplitude (MA). Patients were tested for thrombophilic defects, including deficiencies of antithrombin, protein C and protein S, factor V Leiden, prothrombin G20210A mutation, lupus anticoagulant, antiphospholipid antibodies, and high factor VIII levels.ResultsThrombophilia testing identified a prothrombotic abnormality in 11 patients (58%). Sixteen patients (84%) had one or more transient risk factor. There were no significant differences in TEG parameters between CVT patients and controls, neither between the subgroup of patients with a thrombophilic defect and controls. Seven of all patients (37%), including 5 patients with abnormal thrombophilia testing, and 5 controls (26%) had one or more TEG hypercoagulable parameters.ConclusionsA persistent hypercoagulable state which could have predisposed to venous thrombosis in CVT patients and in the subgroup of patients with a thrombophilic defect could not be demonstrated by TEG.     

Effect of prothrombin 19911 A>G polymorphism on the risk of cerebral sinus‐venous thrombosis

Background and Purpose: The A>G polymorphism at position 19911 of the prothrombin gene is associated with a mildly increased risk of venous thromboembolism, alone or in association with such common thrombophilia mutations as factor V Leiden and prothrombin 20210 GA. Its role in cerebral sinus‐venous thrombosis (CSVT) is not known. Methods: The presence of prothrombin 19911 A>G was investigated in a case–control study of 107 patients with cerebral thrombosis and factor V Leiden (n = 25), prothrombin 20210 GA (n = 47), without known thrombophilia (n = 35) and 842 healthy individuals with the corresponding coagulation profile. Results: Prothrombin 19911 A>G did not increase the risk of CSVT in carriers of factor V Leiden (adjusted odds ratio 1.6, 95%CI 0.6–4.7), prothrombin 20210 GA (odds ratio 1.1, 95%CI 0.6–2.2), nor in patients without known thrombophilia (odds ratio 1.3, 95%CI 0.5–3.1). Conclusions: Prothrombin 19911 A>G polymorphism does not appear to be a risk factor for CSVT, alone or in association with factor V Leiden or prothrombin 20210GA.     

Increased prevalence of factor V Leiden in patients with retinal vein occlusion and under 60 years of age

Retinal vein occlusion (RVO) is a multifactorial disease involving vessel damage, stasis, viscosity and thrombosis. Conflicting findings on hereditary thrombophilic risk factors have been reported and their impact on RVO features remains to be defined. The aim of the present study was to evaluate the prevalence of hereditary thrombophilic risk factors (HTRF) and characteristics of RVO in patients with or without HTRF. The design of the study was a prospective, observational case series. Two hundred and thirty-four patients with RVO were included consecutively. A French healthy population of the same region was studied as control group. The HTRF studied were protein C (PC), protein S (PS) and antithrombin (AT) deficiencies, factor V Leiden (FVL) and factor II 20210A polymorphisms. Chi-Square was used for comparison with the healthy subjects and between RVO patient with and without HTRF according to localisation (branch vs. central), type of RVO (ischemic or non-ischemic), recurrence, age at first event and classical vascular risk factors. Twenty-two patients had HTRF (12 FV Leiden heterozygotes, 9 FII 20210A heterozygotes and 1 PS deficiency). No AT or PC deficiency was detected. Frequencies of PS deficiency, FVL and FII 20210A allele were similar to the reference population as well as to published data in the general caucasian population. Eighty-six patients experienced their first episode before the age of 60 years. Systemic hypertension, glaucoma and angina were significantly less frequent in patients with RVO before 60 years. Fourteen of the 22 patients with one HTRF (64%) experienced their first episode of RVO before the age of 60 years compared to 72 of 212 without HTRF (34%) (p = 0.006). Heterozygote status for FV Leiden was significantly more frequent in patients who had experienced their first episode of RVO before 60 years (p = 0.027). In conclusion, this study suggests a role of FV Leiden in the occurrence of RVO in patients younger than 60 years who exhibit fewer acquired vascular risk factors than in older patients.     

The G20210A prothrombin polymorphism is not associated with increased thromboembolic risk in a large protein C deficient kindred

Likelihood analysis was used to test the effect of the G20210A prothrombin mutation and the His107Pro protein C mutation (resulting from a C insertion) on thrombosis status and prothrombin level in a large kindred of French Canadian descent with type I protein C deficiency. Genotypes were available on 279 pedigree members or their spouses. Of this total, 36 pedigree members were heterozygous for the G20210A variant and one pedigree member was homozygous for G20210A, while 64 were heterozygous for the His107Pro protein C mutation. The factor V Leiden mutation (Arg506Gln) was observed in only one of 181 tested family members. Objectively verified thrombosis was present in 26 of the 279 pedigree members. Thrombosis was suspected in an additional 19 pedigree members. The transmission disequilibrium test of Spielman, 1996, as extended to pedigrees, was used to test for excess transmission of G20210A or His107Pro to thrombosis cases, with transmission of 0.5 specifying no effect. Although the His107Pro mutation was over transmitted (0.837 +/- 0.075 p <0.001) to thrombosis cases in this pedigree, the G20210A variant was not (0.491 +/- 0.130 NS). Measured genotype analysis was used to examine a total of 184 individuals for the relationship between prothrombin level and both the G20210A variant and thrombosis. The G20210A variant increased prothrombin level from 97 +/- 2% to 124 +/- 4% (p <0.0001), but thrombosis status was not associated with any additional increase in prothrombin level. Thus, in a large thrombophilic, protein C deficient kindred, with the G20210A variant present in a proportion (13%) far higher than the general Caucasian population (approximately 2%), neither the presence of the variant nor the plasma concentration of prothrombin were associated with increased risk for thrombosis. These findings contrast with those of others who have established the G20210A variant as a thrombophilic risk factor; and emphasize the complex nature of the multigenic pathogenesis of thrombophilia.     

Homozygous and double heterozygous Factor V Leiden and Factor II G20210A genotypes predispose infants to thromboembolism but are not associated with an increase of foetal loss

Prospective and controlled data about the individual risk profile in asymptomatic children with homozygous or double heterozygous risk genotypes for Factor V Leiden (FVL) and factor II (FII) G20210A are currently unavailable. The systematic and prospective observational study presented here was designed to determine the impact of the homozygous and double heterozygous FVL and FII G20210A genotypes on the prenatal and postnatal risk profiles of affected children. Risk infants and heterozygous controls were identified by screening of 85,304 neonates. Follow-up included the comparison of prenatal and postnatal development, ultrasonography of brain and kidneys, and a panel of independent determinants of thrombophilia. The numbers of identified or expected FVL homozygotes and double heterozygotes did not differ significantly (FVL: 116 versus 91, p=0.08; FVL/FII: 94 versus 76, p=0.17), indicating the absence of a prenatal disadvantage. A prenatal advantage was suggested in FII homozygotes, whose identified number far exceeded the expected (19 versus 4, p=0.002). Clinical and/or imaging abnormalities indicated spontaneous thromboembolic events in 4 of 129 risk infants (3%) but in none of the 178 controls (p=0.02). Physical and neurological development was normal in both groups during the first 2 years of life. The risk genotypes appear to confer a significant predisposition for spontaneous thromboembolic events in infancy without impeding development within the first two years of life. Foetal risk genotypes do not cause an increased foetal loss rate. Moreover, homozygous FII G20210A appears to be associated with a prenatal advantage.     

Thrombophilia testing in patients with venous thromboembolism. Findings from the RIETE registry

BackgroundThere is scarce information on the management habits with regard to thrombophilia testing in patients with venous thromboembolism (VTE).Patients and MethodsRIETE is an ongoing registry of consecutive patients with symptomatic VTE. Aimed to estimate the extent to which thrombophilia test ordering patterns are consistent with the recommendations by a 2005 international consensus statement, we retrospectively compared the clinical characteristics of all patients tested for thrombophilia and those who were not tested.ResultsOf 21367 patients enrolled, 4494 (21%) were tested for thrombophilia: 1456 (32%) tested positive, 3038 (68%) negative. The most common abnormalities were: Factor V Leiden (N = 376), antiphospholipid syndrome (N = 289), and prothrombin G20210A (N = 263). Overall, 12740 (60%) patients met one or more criteria of the consensus statement: 7894 (37%) had a first episode of idiopathic VTE; 4013 (19%) were aged < 50 years; 133 (0.6%) were pregnant women; 758 (3.5%) were using estrogens; 3375 (16%) had recurrent VTE. Of them, 3618 (28%) underwent thrombophilia tests, 34% of whom tested positive. The percentage of patients testing positive was significantly higher in those aged < 50 years, with no differences between idiopathic or secondary, first episode or recurrent VTE. Finally, 876 (10%) of the 8627 (40%) patients meeting no criteria were tested. Of these, 208 (24%) tested positive.ConclusionsTwenty-eight percent of patients meeting one or more criteria for thrombophilia testing, and 10% of those with no criteria were actually tested. Thus, a substantial proportion of thrombophilia ordering is not consistent with the recommendations made by the consensus statement.     

A Novel Mutation (G2172→C) in the Factor V Gene in a Chinese Family with Hereditary Activated Protein C Resistance

BackgroundActivated protein C resistance (APC-R) was a major risk factor for venous thromboembolism(VTE) in Caucasians, and at least 90% of APC-R were associated with the point mutation of factor V (FV) gene (Arg506 → Gln, FV Leiden). However, this genetic defect was extremely rare in Asian population.ObjectiveTo identify the genetic defect of FV in a Chinese family with APC-R associated with VTE.MethodsWe describe a Chinese family with a history of venous thrombosis. Blood samples were obtained from five family members (including the proband) for screening APC-R by coagulation assay and the genetic defect of FV using direct sequencing.ResultsFour out of five members had APC-R. We identified a novel mutation (G2172→C) in exon 13 of the FV gene, which was present in all the individuals with APC-R but was absent in the individual without APC-R. This mutation is predicted to result in the replacement of glutamate by aspartate at position 666, close to one of the APC cleavage sites.ConclusionsWe have identified, for the first time, a novel mutation (G2172→C) of FV that was associated with APC-R in a Chinese family with VTE. We speculate that this mutation interferes with cleavage at Arg679 by APC. The incomplete penetrance of thrombotic phenotype in this family, similar to that conferred by FV Leiden, suggests that it might be a weak risk factor for VTE.     

Identificación de factores de riesgo genéticos asociados a la enfermedad vascular cerebral de tipo isquémico en jóvenes mexicanos

IntroductionNumerous polymorphisms in candidate genes coding for haemostatic system proteins have been proposed as risk factors for thrombosis.MethodsWe performed a case-control study of consecutive ischaemic stroke survivors aged ≤  45 years, treated at our neurology department from 2006 to 2014. Polymerase chain reaction–restriction fragment length polymorphism identified the following polymorphisms: Thr325Ile and Ala147Thr in TAFI, 4G/5G in PAI-1, PLA1/A2 in platelet glycoprotein IIb/IIIa, Glu298Asp in eNOS, and C677T in 5,10-MTHFR. A multivariate logistic regression analysis was performed to evaluate the independent risk of stroke.Results204 cases and 204 age- and sex-matched controls were included in the study. Clinical and genetic variables associated with ischaemic stroke were hypertension (P = .03), tobacco use (P = .02), and the polymorphisms Glu298Asp (genotype: P = .001, allele frequency: P = .001) and C677T (genotype: P = .01); the Ala147Thr, Thr325IIe, 4G/5G, and PLA1/A2 mutations were not associated with ischaemic stroke. The 298Asp (P = .03) and T (P = .01) alleles, hypertension (P = .03), tobacco use (P = .01) and family history of stroke (P = .04) were identified as independent risk factors.ConclusionsThe polymorphisms Glu298Asp and C677T, affecting the eNOS and 5,10-MTHFR enzymes, respectively, and smoking, hypertension, and family history of stroke were associated with ischaemic stroke in young Mexican patients; this was not the case for the Thr325Ile, Ala147Thr, 4G/5G, and PLA1/A2 polymorphisms of the genes coding for fibrinolytic proteins and platelet receptors.     

Combined effect of factor V Leiden and prothrombin 20210A on the risk of venous thromboembolism--pooled analysis of 8 case-control studies including 2310 cases and 3204 controls. Study Group for Pooled-Analysis in Venous Thromboembolism

Factor V Leiden and factor II G20210A mutations are two frequent genetic risk factors involved in venous thromboembolism (VTE). The goal of this pooled analysis of 8 case-control studies, comprising a total of 2310 cases and 3204 controls, was to precisely estimate the risk of VTE in patients bearing both mutations (double heterozygotes). Odds ratios for VTE were 4.9 (95% CI; 4.1-5.9) for the factor V Leiden and 3.8 (3.0-4.9) for the factor II G20210A mutation. Fifty-one cases (2.2%) and none of the controls were double heterozygotes. The odds ratio for venous thrombosis in double heterozygotes was 20.0 (11.1-36.1). Twelve percent of patients heterozygous for factor V Leiden were also heterozygous for factor II G20210A and conversely 23% of patients heterozygous for factor II G20210A were also heterozygous for factor V Leiden. Furthermore, in this large population we analyzed the effect of oral contraceptive (OC) in women carrying one of these mutations. Odds ratio for VTE associated with OC was 2.29 (1.72-3.04). In factor V Leiden carriers using OC, the odds ratio for VTE was 10.25 (5.69-1 8.45). The odds ratio of the association of factor II mutation and OC use was 7.14 (3.39-15.04). Finally, we also confirmed that the frequency of factor V Leiden was lower in patients with pulmonary embolism than in patients with deep vein thrombosis without PE (odds ratio 0.69). Conversely, factor II G20210A mutation was equally balanced in both patient groups.     

Protein C global assay in the evaluation of women with idiopathic pregnancy loss

A number of strongly linked polymorphisms within the Factor V gene (FV HR2 haplotype) has been identified as a cause of resistance to activated protein C, and has suggested a modest risk factor for vein thrombosis. We investigated the frequency of the HR2 haplotype in 433 consecutive patients with confirmed deep vein thrombosis and 326 controls. The HR2 haplotype was more frequent in patients (15.2%) than in controls (10.1%). The risk of thrombosis among carriers of this haplotype was significantly increased (odds ratio: 1.6 [95% CI: 1.0-2.5]). The estimated risk associated with the HR2 haplotype was 1.8 (95% CI: 1.1-2.9) in subjects with (n = 255), and 1.4 (95% CI: 0.8-2.4) in those without (n = 178) acquired risk factors for vein thrombosis. After adjustment for sex, FV Leiden and FII A20210 mutations, the estimated risk of vein thrombosis among carriers of the HR2 haplotype was 1.8 (95% CI: 1.1-2.8). Present data indicate that the HR2 haplotype is independently associated with vein thrombosis among individuals with a high-risk profile.     

Venous thromboembolism in carriers of the Factor V Leiden mutation and in patients without known thrombophilic risk factor; prediction of recurrence and APC-PCI complex concentration and/or soluble thrombomodulin antigen and activity

BACKGROUND: The complex between activated protein C (APC) and the protein C inhibitor (PCI) is a sensitive indicator of the degree of activation of blood coagulation and higher concentrations have been measured in carriers of the FV Leiden mutation who were in the recovery phase after treatment for venous thromboembolism (VTE). OBJECTIVES: The main purpose of this study was to correlate the APC-PCI complex concentration to thrombomodulin activity and antigen concentration in the same group of patients. We also add a prospective clinical follow-up of the VTE recurrence after 1 year to investigate if the markers can predict the risk for a new VTE. PATIENTS/METHODS: Blood samples were collected from 50 patients with the FV Leiden mutation and 132 without any known risk factor for thrombophilia after finished treatment. RESULTS: The APC-PCI complex, s-TM activity and the quotient (s-TM activity)/(s-TM antigen) were higher in VTE patients with FV Leiden. In total, there were 19 VTE recurrences (10%) after 1 year. The OR for recurrence was 1.9 (95% CI 0.68-5.0) in all VTE patients with elevated APC-PCI complex (above 75th percentile) and 3.6 (95% CI 1.1-12) in VTE patients without any known risk factor for thrombophilia and with elevated s-TM activity. CONCLUSION: The APC-PCI complex concentration, s-TM activity and the quotient (s-TM activity)/(s-TM antigen) were higher in VTE patients with FV Leiden. The s-TM activity showed higher OR for recurrence of VTE in patients without known thrombophilic risk factor. Both methods could be sensitive markers of increased risk for venous thrombosis.     

Markers of activated coagulation in patients with factor V Leiden and/or G20210A prothrombin gene mutation

The activated protein C (APC) resistance phenotype associated with an abnormal factor V Leiden (FVL), and the G20210A prothrombin gene mutation are the most common findings in patients with venous thromboembolism (VTE). In a group of 210 patients, we compared the levels of markers of coagulation activation in carriers of FVL (71 heterozygous, 30 homozygous), G20210A prothrombin mutation (88 heterozygous) or both mutations combined (21 heterozygous), in order to assess whether these markers allow identification of a group of patients with a higher risk of thrombosis; they were also compared to normal values. A total of 143 patients had a personal history of VTE and 67 were asymptomatic. None of them had other hereditary causes of thrombophilia or an antiphospholipid syndrome. None were currently treated with either anticoagulant or hormonal treatment. Pregnant women were excluded.No significant difference between the four groups of patients could be found in the levels of F1+2, TAT and DDI. Levels were all significantly higher than the control values (p<0.05).The levels of F1+2 and TAT were similar in patients with or without a history of VTE, regardless of the type of mutation. DDI levels were significantly higher in patients with a history of VTE than in asymptomatic subjects (443+/-248 vs. 333+/-222 ng/ml, p=0.02) but with only 57% sensitivity and specificity. In conclusion, our study confirms the hypercoagulable state found in mutation carriers and points out the inability of F1+2 and TAT assays to identify a group of subjects at higher risk of thrombosis, within carriers of genetic risk factors. Although the sensitivity and specificity of DDI assay are low, high DDI concentrations tend to be associated with the risk of VTE.     

Screening for thrombophilic risk factors among 25 German patients with cerebral venous thrombosis

OBJECTIVES: In this study the frequency of inherited thrombophilic risk factors in a population of German CVT patients and their influence on clinical outcome were evaluated. MATERIAL AND METHODS: Twenty-five patients (age 37.1 +/- 16.3 years) with CVT were screened for inherited coagulation disorders. All participants received a full clinical follow-up (mean follow-up period 4.8 +/- 6.4 years). RESULTS: Inherited thrombophilic risk factors were identified in 9 (36%) of the 25 patients studied. Four were found positive for the heterozygous factor V Leiden mutation, 2 were heterozygous carriers of the prothrombin-G20210A-polymorphism. APC resistance proved to be a reliable screening method for factor V Leiden mutation, whereas genetic evaluation for protein S and C deficiencies failed to demonstrate any mutations despite the identification of 1 patient with a protein C and protein S deficiency each. One patient suffered from a familial plasminogen deficiency. These 9 patients had a less favorable outcome (P < 0.05). CONCLUSION: Our results demonstrate that screening for inherited thrombophilia should be an integral part in the diagnostic work up of CVT patients. Patients with inherited coagulopathies tended to have a less favorable outcome, corroborating recommendations for a longer period of oral anticoagulation.     

Analysis of the LRRK2 Gly2385Arg variant in Alzheimer's disease in Taiwan

ObjectiveTo analyze the Gly2385Arg (G2385R) mutation in Taiwanese Alzheimer's disease (AD) patients.BackgroundThe leucine-rich repeat kinase 2 (LRRK2) gene is well known to predispose subjects to Parkinson's disease (PD). The Gly2385Arg (G2385R) variant of LRRK2 is believed to be “East Asian”-specific, particularly in the Han Chinese population; however, whether the LRRK2 G2385R is associated with a risk of AD in pure Han-Chinese patients has not often been studied.MethodsA total of 209 AD patients (87 men, 122 women) and 180 age- and gender-matched controls were recruited and the demographic data of the AD patients were analyzed. Genotyping of the Gly2385Arg variant was studied using matrix-assisted laser desorption/ionization time-of-flight (MALDI-TOF) mass spectrometry.ResultsSubjects with the Gly2385Arg variant were all heterozygous carriers. The frequency of Gly2385Arg carriers did not differ significantly between the AD patients and controls (4.78% versus 4.44%, odds ratio = 1.04, 95% CI = 0.62–1.77, P = 0.87). In the AD patient group, the age of symptom onset, the length of education, or the MMSE score showed no significant differences between wild-type carriers and heterozygous variant carriers (P = 0.51, 0.43, and 0.09).ConclusionThe Gly2385Arg variant of LRRK2 may not be a major risk factor for AD in pure Han Chinese patient. Among the AD patients, Gly2385Arg carriers were not clinically different from wild-type carriers.     

Mutations and polymorphisms in genes affecting hemostasis proteins and homocysteine metabolism in children with arterial ischemic stroke

BACKGROUND: The pathogenesis of thrombosis in childhood seems to be multifactorial implicating genetic and environmental factors. AIM: To compare the distributions of mutations/polymorphisms in genes affecting hemostasis (factor V Leiden - FVL, FV H1298R-FVR2, FII 20210A, b-Fib 455G>A, FXIII V34L, PAI-1 4G, HPA-1b) or homocysteine metabolism (MTHFR C677T, MTHFR A1298C) among 90 children with arterial ischemic stroke (AIS) and 103 controls, and to associate the carriage of these mutations/polymorphisms with their corresponding proteins in children with AIS. RESULTS: AIS was more frequent in boys (p < 0.01). No studied mutation/polymorphism was found to be a risk factor for AIS, except for FVL [odds ratio 4.2 (95% CI 1.5-12.1)], the presence of which was even higher in 31 children with congenital AIS [odds ratio 6.82 (95% CI 2.0-22.8)]. FVL carriers had an odds ratio of 5.76 (95% CI 1.6-6.4) when FVR2 was absent. In thrombosed children, activated protein C resistance, prothrombin and fibrinogen levels were higher in the presence of FVL, FII20210A or b-Fib 455G-->A, respectively. Double heterozygotes in both MTHFR C677T and A1298T or homozygotes in one had significantly elevated homocysteine levels. CONCLUSION: Except for FVL, no definite conclusion could be reached regarding the involvement of the studied mutations/polymorphisms in childhood AIS.