Haplotypes of TAFI gene and the risk of cerebral venous thrombosis - a case-control study

Introduction

Cerebral venous thrombosis (CVT) is an uncommon disease with some differences compared to other-site thrombosis, including a higher frequency in young people, female sex and oral contraceptive users. Thrombin-activatable fibrinolysis inhibitor (TAFI) is a regulator of fibrinolysis, whose levels are genetically controlled and its increase is associated to thrombosis. Our objective was to investigate in a case-control study the association between CVT and TAFI single nucleotide polymorphisms (SNPs) and its haplotypes in comparison to other-site venous thrombosis and controls.

Materials and Methods

Seventy two patients with CVT were compared to 143 individuals with no history of thromboembolic events (control group) and to 128 patients with deep vein thrombosis in the limbs and/or pulmonary embolism (venous thromboembolism-VTE group). SNPs were genotyped by restriction fragment length polymorphism or allele-specific PCR for F2 20210G > A, F5 1691G > A, TAFI (-1053C > T, -438G > A, 505G > A, 1040C > T and + 1542C > G).

Results

The GTC haplotype for TAFI 505G > A/1040C > T/+ 1542C > G SNPs was associated with an increased risk of CVT compared to controls [odds ratio (OR) 2.67, 95% confidence interval (CI): 1.13 - 6.34) and VTE group (OR 2.51, 95%CI: 1.07 - 8.06). The CVT risk became even more pronounced when evaluating unprovoked or hormone-related thrombosis cases: CVT compared to controls (OR 3.24, 95%CI: 1.19 - 8.82) and VTE group (OR 4.32, 95%CI: 1.27 - 14.63).

Conclusions

Our data indicate that the GTC haplotype for TAFI 505G > A/1040C > T/+ 1542C > G SNPs increased the risk of CVT in comparison to controls and VTE cases. Further studies are required to confirm our findings.     

Headache in patients with cerebral venous thrombosis

Headache is the most frequent symptom of cerebral venous thrombosis. They do not have particular characteristics and can mimic other numerous varieties of headache. Frequently associated with other neurological symptoms, such as intracranial hypertension, seizures, focal deficits or disorders of consciousness, they are sometimes isolated, which stresses the need for investigations in all recent and unusual headache.     

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.     

Thrombophilic gene polymorphisms in puerperal cerebral veno-sinus thrombosis

Puerperal cerebral veno-sinus thrombosis (PCVT) is a common form of stroke in young women in India, which is associated with high morbidity and mortality. The frequency of PCVT in India is 10 to 12 times more compared to western population. As yet, the etiology of this condition is unclear. Our aim was to study the prevalence and the role of the common genetic polymorphisms associated with thrombophilia such as factor V Leiden, prothrombin G20210A and methylene tetrahydrofolate reductase (MTHFR) C677T, in aseptic PCVT. We investigated 86 women with PCVT and 86 age-matched women with no post-partum complications. Polymerase chain reaction (PCR)/restriction fragment length polymorphism analysis was used to identify their genotypes. The frequency of the three polymorphisms in cases and controls were: factor V Leiden, 2.3% versus 1.2% (OR 0.49, 95% CI=0.02-7.12, p=1.000) and MTHFR C677T, 16.3% versus 17.4% (OR 0.92, 95% CI=0.39-2.19, p=0.838). The prothrombin G20210A variant was not detected in either patients or controls. The clinical characteristics of the PCVT patients with the polymorphisms did not differ significantly from those without them. In our series of PCVT patients, the risk associated with the established thrombophilic risk factors is insignificant. Exploration of these gene polymorphisms seems to be of limited value in the investigation of PCVT in south Indian women.     

颅内静脉血栓形成的临床特点分析

目的探讨颅内静脉血栓形成（CVT）的病因、临床特点、诊断、治疗。方法回顾性分析12例CVT患者的临床资料,并结合文献分析。结果12例CVT患者中8例病因明确,临床表现以头痛伴恶心呕吐、视乳头水肿为主,脑脊液（CSF）检查以压力升高为主要特点,D-二聚体（DD）检查有62.5%的患者高于正常,CT主要表现局限性脑梗死及脑水肿,MRI联合MRV表现静脉窦闭塞者占91.7%,病因及脱水、溶栓、抗凝治疗疗效较好。结论CVT临床表现复杂多样,产褥期、感染、白塞病可继发CVT,MRI和MRV相结合诊断率高,肝素抗凝为首选治疗。     

Risk of cerebral venous thrombosis and novel gene polymorphisms of the coagulation and fibrinolytic systems

BACKGROUND AND PURPOSE: Genetic thrombophilic conditions such as those associated with Factor V Leiden (FVL) and the prothrombin mutant (PT G20210A) have been identified as risk factors for cerebral venous thrombosis (CVT). Recently, a single nucleotide polymorphism (SNP) of the thrombin activatable fibrinolysis inhibitor (TAFI G-438A) has been shown to be associated with lower TAFI levels and to decrease the risk for peripheral venous thrombosis. Furthermore, a protective role in juvenile stroke was shown for a SNP of the vitamin K dependent protein Z (PZ Intron F G79A) which is linked with low PZ levels. PATIENTS AND METHODS: In 77 consecutive patients with CVT and in 203 randomly selected population controls from the same region of Southern Germany, we investigated the following functional SNPs using PCR and restriction fragment analysis techniques: TAFI G-438A, PZ Intron F G79A, FVL and PT G20210A. RESULTS: The prevalence of FVL tended to be higher (OR 2.08, 95 % CI 0.91-4.75, p = 0.06) and that of PT G20210A (OR 4.57, 95 % CI 1.45-14.44, p = 0.007) was significantly higher in patients with CVT than in controls. The A-allele frequency of the TAFI G-438A polymorphism did not significantly differ between patients (21.3 %) and controls (26.9%; OR 0.71, 95 % CI 0.45-1.12; p = 0.17). For the PZ G79A SNP, the frequency of the A-allele was 19.5% in CVT and 24.6% in controls (OR 0.77, 95 % CI 0.49-1.21; p = 0.31). CONCLUSIONS: In this large series of CVT patients, a positive association with established thrombophilic risk factors FVL and especially the PT G20210A mutation was confirmed. In contrast, our study found no significant association of CVT with SNPs of the TAFI and the PZ genes. Other than testing for FVL and the PT G20210A mutation, exploration of these potential thrombophilic variants seems to be of limited value in the investigation of CVT.     

350例脑静脉窦血栓患者临床特点研究

目的分析350例脑静脉窦血栓形成患者临床特点,为脑静脉窦血栓形成患者的诊治提供新思路。方法 2004-2014年间在我院经临床和影像学诊断符合的脑静脉窦血栓患者350例,详细采集并记录患者的临床表现、个人及家族史、实验室检查、影像学检查;从人口资料、病因、症状、体征、影像学表现等方面进行系统的归纳分析。结果 350例患者中,男性148例(42.3%),女性202例(57.7%),平均发病年龄为(35.51±12.07)岁;急性起病41例(12%),亚急性起病95例(27%),慢性214例(61%)。病因方面,256例(73.1%)患者无明确病因;94例(26.9%)发现可能原因,如妊娠产褥、口服避孕药、头部和耳鼻感染等。临床表现方面,主要首发症状为头痛238例,视力下降82例;主要体征为视乳头水肿156例。腰穿检查的319例患者中,颅内压在70~760 mm Hg,均值为308.6±86.1 mm Hg;38%的病例脑脊液常规出现异常,57%的病例脑脊液生化出现异常。影像学检查的312例患者中,仅一个部位的静脉窦发生血栓者有109例(34.9%),2个及2个以上者为203例(65.1%)。有多达267例(86%)患者无脑实质受损,仅有45例(14%)例有脑实质病变。结论脑静脉窦血栓好发于青年,大多数无明确原因,高颅压是首要和主要临床表现,血栓好发于上矢状窦和横窦,且多数同时发生于多个部位,大多数不伴有脑实质受累。     

Monitoring of venous hemodynamics in patients with cerebral venous thrombosis by transcranial Doppler ultrasound

OBJECTIVES: To test the assumption that transcranial Doppler ultrasound (TCD) is able to detect and to monitor intracranial venous blood flow velocities in patients with confirmed cerebral venous thrombosis (CVT). DESIGN: Prospective case study in 18 patients. SETTING: Inpatient neurologic service in a university hospital. SUBJECTS AND METHODS: Serial TCD examinations were performed in 18 consecutive patients with CVT (14 females, 4 males) aged 16 to 64 years (mean+/-SD, 36.8+/-13.1 years) during a mean follow-up ranging from 34 to 783 days (mean+/-SD, 201+/-185 days) between 1993 and 1997. Venous TCD was performed with a 2-MHz range-gated transducer. RESULTS: Venous blood flow velocities were successfully measured in all patients. The highest measured velocities in the monitored intracranial venous vessels ranged from 20 to 150 cm/s (mean+/-SD, 58.9+/-38.8 cm/s), and the lowest were from 9 to 84 cm/s (mean+/-SD, 27.9+/-17.0 cm/s). Fifteen patients (83%) showed a decrease of velocities-2 of them after a transient increase during cessation of heparin therapy. The percentage of velocity decrease ranged from 34% to 73% (mean+/-SD, 56.4%+/-10.9%). A plateau phase, defined as no further decrease in velocities, was reached in these patients within 4 to 314 days (mean+/-SD, 59.9+/-73.7 days). Three patients (17%) showed no changes in velocities as defined by a limit of velocity variation of 30% during the course of CVT. High venous velocities were significantly associated with altered consciousness (P = .001). A nonsignificant relationship was observed with affliction of the superior sagittal sinus. No correlations were noted for onset of disease, initial motor deficits, and presence of bleeding. No predictive value was gained from analyzing the outcome in relation to absolute velocities or their decrease. CONCLUSIONS: Serial TCD studies allow monitoring of venous hemodynamics and collateral pathways in patients with CVT. Normal venous velocities in serial measurements, however, do not exclude a diagnosis of CVT.     

Methylenetetrahydrofolate reductase gene polymorphisms in patients with cerebral hemorrhage

Elevated plasma total homocysteine (HCY) level is a risk factor for coronary heart disease and ischemic stroke. We investigated relationships between polymorphisms in the methylenetetrahydrofolate reductase (MTHFR) gene, and plasma levels of HCY and folate in patients of Mongolian races who suffered from cerebral ischemia (CI, n = 42) or cerebral hemorrhage (CH, n = 20) and in the 24 age-matched controls. The incidences of both homozygous and heterozygous MTHFR gene mutations in CI (26 and 43%) and in CH (25 and 60%) were significantly higher than those in the controls (8 and 25%). Homozygous MTHFR gene mutation was associated with reduced plasma folate levels, but not with increased plasma HCY levels. Among the subjects with homozygous MTHFR gene mutation, plasma folate levels in CH was significantly lower than those in CI and controls. MTHFR gene mutation in CH was found to be as common as that in CI and was associated with reduced plasma folate levels in the both. In homozygous MTHFR gene mutation, the plasma folate level was profoundly reduced in CH as compared with CI and controls, suggesting that subjects with low plasma folate levels have a predisposition to intracerebral bleeding.     

Headache in cerebral venous thrombosis

Neurological Sciences - In the past, cerebral venous thrombosis (CVT) was considered a rare, devastating disease. The widespread use of angiography, magnetic resonance imaging (MRI) and magnetic...     

脑深静脉血栓形成两例临床和病理报告

目的：分析脑深静脉血栓形成（DCVT）的临床和病理物点。方法：分析2例患者的临床床及尸检资料,结果：本病临床常表现呼精神障碍。CT、CT血管造影（CTA）、MRI和磁共振血管造影（MRA）等使早期临床诊断成为可能。早期诊断抗凝、溶栓治疗使本病预后趋于良好。DCVT往往累及整个深静脉表现各异,首发症状多为头痛、意识和精神障碍,CT检查显示双侧基底节或丘脑梗死;CTA或MRI（MRA）检查能够辅助临床诊断,早期抗凝和溶栓治疗使预后趋于良好。     

尿激酶联合替罗非斑在颅内静脉窦血栓形成介入性治疗中的应用

目的 探讨尿激酶联合替罗非斑血管内溶栓治疗颅内静脉窦血栓形成(CVST)的疗效和安全性. 方法 广州军区武汉总医院神经外科自2009年1月至2011年1月行尿激酶联合替罗非斑经微导管选择性静脉窦内溶栓、机械性碎栓治疗9例重症CVST患者,分析其临床资料和疗效. 结果 出院前8例患者脑脊液(CSF)压力正常,DSA检查显示7例患者静脉窦主干通畅,皮层静脉和深静脉恢复正常.1例部分再通,皮层静脉部分代偿.术中和术后未发生手术操作相关的并发症;出院时8例患者症状、体征得到改善,其中头痛消失7例,遗留轻度头痛1例.1例死亡. 结论 尿激酶联合替罗非斑经微导管选择性静脉窦内溶栓治疗是CVST安全、有效的治疗手段.     

Neurological and cognitive long-term outcome in patients with cerebral venous sinus thrombosis

OBJECTIVES: The main aim of the present study was to assess long-term neurological and cognitive outcome in patients with cerebral venous sinus thrombosis (CVST). METHODS: We re-investigated by means of a face to face interview all patients with a confirmed diagnosis of CVST, collected at our Department over the years 1990-2000. During the interview the presence of headache, epileptic seizures, visual deficits and a new episode following the first occurrence of CVST were checked. Moreover all patients underwent a neurological examination, a functional evaluation, a cognitive assessment to rule out aphasia, apraxia and working memory deficits. Depression of mood was also investigated. RESULTS: On the whole 34 patients entered the study: 10 patients referred episodic headache following the disease. In three cases epileptic seizures were present. A new event occurred in only one patient. Four patients showed pyramidal signs, in two cases visual deficits were present. All patients had no functional disability. We found a mild non-fluent aphasia in three patients, working memory deficits in six patients and depression of mood in six cases. CONCLUSION: The present study demonstrates a good neurological and cognitive long-term outcome in patients with CVST.