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.     

小鼠体内血栓形成动物模型的建立及在抗血栓药物筛选中的应用

目的 :建立一种无创性小鼠体内血栓动物模型并应用于多种抗血栓药物的药效观察。方法 :用角叉菜胶建立了小鼠体内血栓动物模型。利用此模型观察潘生丁片 ,抗栓胶囊、复方丹参注射液、川芎嗪注射液对血栓形成的影响。结果及结论 :用角叉菜胶建立的小鼠体内血栓动物模型 ,无创伤性 ,操作简易方便。并可应用于多种抗血栓药物的药效观察 ,剂量的选择 ,药物的筛选。     

Deep venous thrombosis and occult malignancy: an epidemiological study.

OBJECTIVE--To determine the risk of subsequent cancer in patients with deep venous thrombosis confirmed by venography. DESIGN--Follow up of all patients who had venography for suspected deep venous thrombosis during 1984-88. Patients were traced through a cancer registry up to 1 January 1991. SUBJECTS--4399 patients who had phlebography in one hospital. SETTING--General hospital in Malmö, Sweden, serving a population of 230,000. MAIN OUTCOME MEASURE--Number of cancers recorded. RESULTS--4399 patients had venography for suspected deep venous thrombosis; 604 were known to have a malignancy at the time of venography and were excluded from further analysis. 1383 had deep venous thrombosis, 150 of whom subsequently developed cancer. 182 of the 2412 patients without thrombosis developed cancer. During the first six months after venography 66 patients with thrombosis developed malignancy compared with 37 patients without thrombosis (P < 0.0001). 38 of the cancers in the deep venous thrombosis group were detected by history, physical examination, and laboratory tests. Three patients had postoperative or post-traumatic deep venous thromboses. Only two of the remaining patients would have benefited from early detection by extensive screening. After six months the incidence of cancer was identical in patients with and without thrombosis. CONCLUSION--Deep venous thrombosis is associated with a significantly higher frequency of malignancy during the first six months after diagnosis. Malignancies can be found with simple clinical and diagnostic methods and extensive screening is not required.     

Genetic Polymorphism of NOS3 with Susceptibility to Deep Vein Thrombosis after Orthopedic Surgery: A Case-Control Study in Chinese Han Population

Deep vein thrombosis is one of the common complications of orthopedic surgery. Studies indicated that genetic factors played a considerable role in the pathogenesis of deep vein thrombosis. Endothelial nitric oxide synthase which encoded by nitric oxide synthase 3 (NOS3), can generate nitric oxide in endothelial cells. As a predominant regulator for vascular homeostasis, nitric oxide might be involved in the pathogenesis of thrombosis. It had been proved that the NOS3 polymorphism (rs1799983) was associated with the development of cardiovascular diseases. Our objective was to evaluate the association between the NOS3 polymorphism (rs1799983) and deep vein thrombosis after orthopedic surgery in Chinese Han population. The polymorphism was genotyped in 224 subjects with deep vein thrombosis after orthopedic surgery and 580 controls. Allele and genotype frequencies were compared between subjects with deep vein thrombosis and control subjects. The allele and genotype frequencies of the NOS3 polymorphism (rs1799983) were significantly different between subjects with deep vein thrombosis and control subjects. There were also significant differences when the subjects were stratified by gender, surgery type and hypertension status. These findings suggested that the NOS3 polymorphism (rs1799983) was associated with susceptibility to the deep vein thrombosis after orthopedic surgery in Chinese Han population, and NOS3 might play a role in the development of deep vein thrombosis after orthopedic surgery.     

Diagnostic Accuracy in Venous Thrombosis

A group of 111 surgical patients at high risk of venous thrombosis were studied after operation by independent clinical assessment and with ¹²⁵I-fibrinogen to detect venous thrombosis. Almost half of the patients developed venous thrombosis. Of these, two-thirds were not suspected clinically despite careful scrutiny. In the patients in whom a clinical diagnosis of venous thrombosis was made this diagnosis was falsely positive in a quarter. More than half of all thrombotic episodes were detectable on the day after operation.The prevalence of venous thrombosis, together with the difficulty in diagnosing it, strongly supports the argument that a reduction in the incidence of pulmonary embolism must depend on widespread adoption of effective prophylaxis, especially in the large number of patients at high risk of venous thrombosis. Prophylactic trials must be objectively assessed, and it is in this field that the ¹²⁵I-fibrinogen technique probably has the most to offer.     

Increased risk of venous thrombosis by AB alleles of the ABO blood group and Factor V Leiden in a Brazilian population

Most cases of a predisposition to venous thrombosis are caused by resistance to activated protein C, associated in 95% of cases with the Factor V Leiden allele (FVL or R506Q). Several recent studies report a further increased risk of thrombosis by an association between the AB alleles of the ABO blood group and Factor V Leiden. The present study investigated this association with deep vein thrombosis (DVT) in individuals treated at the Hemocentro de Pernambuco in northeastern Brazil. A case-control comparison showed a significant risk of thrombosis in the presence of Factor V Leiden (OR = 10.1), which was approximately doubled when the AB alleles of the ABO blood group were present as well (OR = 22.3). These results confirm that the increased risk of deep vein thrombosis in the combined presence of AB alleles and Factor V Leiden is also applicable to the Brazilian population suggesting that ABO blood group typing should be routinely added to FVL in studies involving thrombosis.     

MiR-296-5p ameliorates deep venous thrombosis by inactivating S100A4

Deep venous thrombosis is one of the most common venous thromboembolic diseases and has a low cure rate and a high postoperative recurrence rate. Furthermore, emerging evidence indicates that microRNAs are involved in deep venous thrombosis. miR-296-5p is an important microRNA that plays a critical role in various cellular functions, and S100A4 is closely related to vascular function. miR-296-5p is downregulated in deep venous thrombosis patients, and its predicted target S100A4 is upregulated in deep venous thrombosis patients. Therefore, it was hypothesized that miR-296-5p may play a vital role in the development of deep venous thrombosis by targeting S100A4. An Ox-LDL-stimulated HUVEC and deep venous thrombosis mouse model was employed to detect the biological functions of miR-296-5p and S100A4. Dual luciferase reporter assays and pull-down assays were used to authenticate the interaction between miR-296-5p and S100A4. ELISA and Western blotting were employed to detect the protein levels of thrombosis-related factors and the endothelial-to-mesenchymal transition (EndMT)-related factors. The miR-296-5p levels were reduced, while the S100A4 levels were enhanced in deep venous thrombosis patients, and the miR-296-5p levels were negatively correlated with the S100A4 levels in deep venous thrombosis patients. miR-296-5p suppressed S100A4 expression by targeting the 3ʹ UTR of S100A4. MiR-296-5p knockdown accelerated ox-LDL-induced HUVEC apoptosis, oxidative stress, thrombosis-related factor expression, and EndMT, while S100A4 knockdown antagonized these effects in ox-LDL-induced HUVECs. S100A4 knockdown reversed the effect induced by miR-296-5p knockdown. Moreover, the in vivo studies revealed that miR-296-5p knockdown in deep venous thrombosis mice exacerbated deep venous thrombosis formation, whereas S100A4 knockdown had the opposite effect. These results indicate that elevated miR-296-5p inhibits deep venous thrombosis formation by inhibiting S100A4 expression. Both miR-296-5p and S100A4 may be potential diagnostic markers and therapeutic targets for deep venous thrombosis.     

78例脑血栓患者清栓酶治疗前后体外血栓形成变化分析

本文对比了用清栓酶治疗前后脑血栓患者体外血栓形成各因素的变化,其中发现脑血栓患者治疗前体外血栓长度,湿干重量与健康人相比增长,加重[P<0.05或<0.01]。而清栓酶治疗后脑血栓患者体外血栓长度,湿干重量与治疗前相比明显降低(P<0.01)。从而证实了清栓酶具有降低血栓形成因子,抗血栓形成,改善微循环之功效。     

Circulating and tissue microRNAs as a potential diagnostic biomarker in patients with thrombotic events

Venous and arterial thrombosis are conditions that have a considerable burden if left untreated. The hypoxia-induced by the occluded vessel can disrupt the circulation of any organ, the cornerstone of treating thrombosis is rapid diagnosis and appropriate treatment. Diagnosis of thrombosis may be made by using laboratory tests or imaging techniques in individuals who have clinical manifestations of a thrombotic event. The use of serum micro ribonucleic acids (RNAs) has recently been applied to the diagnosis of thrombosis. These small RNA molecules are emerging as new diagnostic markers but have had very limited applications in vascular disease. Most of the articles provided various microRNAs with different levels of accuracy. However, there remains a lack of an appropriate panel of the most specific microRNA in the literature. The purpose of the present review was to summarize the existing data on the use of microRNAs as a diagnostic biomarker for venous thrombosis.     

Pacemaker Lead Induced Inferior Vena Caval Thrombosis Leading to Portal Hypertension

Inferior vena caval thrombosis is an unusual complication of permanent pacemaker implantation. The clinical presentation due to thrombosis depends on the site of thrombus. We have described here a rare case of pacemaker lead associated thrombosis of inferior vena cava, its diagnostic work up and briefly reviewed the existing literature of this uncommon complication.     

Case-control study of risk of cerebral sinus thrombosis in oral contraceptive users who are carriers of hereditary prothrombotic conditions

Objective: To investigate whether users of oral contraceptives who are carriers of a hereditary prothrombotic condition (factor V Leiden mutation, protein C, S, or antithrombin deficiency) have an increased risk of cerebral sinus thrombosis. Design: Comparison of a prospective series of cases of cerebral sinus thrombosis with population data. Setting: Neurological teaching hospitals from different regions in the Netherlands (cases) and a representative sample of the non-institutionalised Dutch population (controls). Subjects: 40 women aged 18-54 years with cerebral sinus thrombosis (cases) and 2248 women aged 18-49 years (controls). Main outcome measure: Current use of oral contraceptives at the time of the thrombosis (cases) or at the time of the questionnaire (controls). Prevalences of a hereditary prothrombotic condition in patients and in the population with odds ratios. Results: 34 of 40 (85%) women with cerebral sinus thrombosis used oral contraceptives, versus 1007 of 2248 (45%) of the control women; the age adjusted odds ratio was 13 (95% confidence interval 5 to 37). Seven of 36 patients (19%) had a prothrombotic deficiency, versus 7% expected in the population; this corresponds to a threefold to fourfold increase in risk. In women who used oral contraceptives and also carried a prothrombotic defect, the odds ratio for cerebral sinus thrombosis was about 30 relative to women who had neither risk factor. Conclusion: The use of oral contraceptives and being a carrier of a hereditary prothrombotic condition increase the risk of and interact in a multiplicative way in the development of cerebral sinus thrombosis.

Key messages

• The use of oral contraceptives is associated with an increased risk of cerebral venous sinus thrombosis
• This risk of cerebral venous sinus thrombosis in women who use oral contraceptives is larger if there is an additional hereditary prothombotic factor (protein C, S, or antithrombin deficiency, factor V Leiden mutation)
• The association between oral contraceptives, thrombophilia, and deep vein thrombosis is also valid for cerebral sinus thrombosis
• Women do not need to stop using oral contraceptives as the absolute risk of cerebral sinus thrombosis is very small

     

Diagnosis and treatment of venous thromboembolism by consultants in Scotland.

A questionnaire was sent to 508 consultants in Scotland likely to encounter deep vein thrombosis and pulmonary embolism to assess their current standard practice in diagnosis and treatment of these disorders. Replies were received from 358 (70.5%). In deep vein thrombosis 47% and in pulmonary embolism 33% of consultants usually depended on clinical observation alone for diagnosis. In deep vein thrombosis 37% used venography to supplement clinical diagnosis and in pulmonary embolism 13% used angiography and 53% used isotopic scanning. Almost all consultants treated deep vein thrombosis (95%) and pulmonary embolism (99%) with anticoagulants. Most consultants (81%) gave heparin by intravenous infusion. Although many consultants gave intravenous heparin for more than three days (49.5% in deep vein thrombosis and 61% in pulmonary embolism), 25% of these consultants did not use any laboratory monitoring of heparin''s effect. Large numbers of consultants gave warfarin for more than three months (20% in deep vein thrombosis and 47% in pulmonary embolism). There was a significant tendency to give heparin (p less than 0.01) and warfarin (p less than 0.001) for longer periods in pulmonary embolism than in deep vein thrombosis. This survey shows a widely varying practice and underlines the need for further controlled studies to provide clear guidance in the management of deep vein thrombosis and pulmonary embolism.     

Involvement of bioantioxidants in thrombosis in mice

SUMMARY

An involvement of free radicals in thrombosis has been suggested previously. In order to further explore the role of free radicals and antioxidants in thrombosis, we have measured preventive (enzymes of the glutathione redox cycle) and chain-breaking antioxidants (vitamin E and C) in whole blood, platelets, neutrophils (PMNLs), heart and lung following collagen and adrenaline induced thrombosis in mice. A significant decrease in platelet glutathione (GSH) level (54%) and glutathione reductase activity was observed after thrombosis. In addition, GSH content in whole blood was also found to be reduced. In PMNLs, an increase in glutathione peroxidase activity and a four-fold elevation in vitamin C content was observed following thrombosis. However, levels of vitamin E and total thiol groups remained unchanged in both the cells and tissues. The results further suggest involvement of free radicals and PMNLs in thrombosis.     

Postmenopausal hormone replacement therapy and venous thromboembolism

Background:Women taking hormone replacement therapy (HRT) have a 2- to 5-fold increased risk of venous thrombosis compared with nonusers. Increasingly, evidence has suggested that the size of the risk increase varies according to related factors, such as the type of estrogen used, the mode of delivery, and the presence of other predisposing factors.Objective:The aim of this study was to examine the current literature to assess the varying risk of venous thrombosis among women taking HRT.Methods:An extensive search was carried out on all major electronic databases including MEDLINE 1995 to October 2005 and BIS (EMBASE) 1980 to October 2005. Relevant keywords relating to thrombosis (venous thromboembolism, venous thrombosis, deep vein thrombosis, and pulmonary embolism) combined with hormones (hormone replacement therapy and estrogen) were used to capture all potentially relevant studies.Results:The increased risk of a first episode of venous thrombosis in women currently taking HRT compared with nonusers ranged from 1.22 (95% CI, 0.76–1.94) to 4.50 (95% CI, 1.30–15.10). Similar increases in risks for deep vein thrombosis and pulmonary embolism were found. The risk of venous thrombosis is the highest in the first year of therapy, durich which as much as a greater than 6-fold increase was found. Women taking estrogen-progestin HRT had a significantly greater risk of venous thrombosis than those using estrogen-only preparations (odds ratio [OR], 1.60; 95% CI, 1.13–2.26). Studies have also suggested a dose-related effect, suggesting high-dose estrogen therapy is associated with a greater increased risk of venous thrombosis than low-dose preparations. Comparisons between oral and transdermal HRT have shown a significant difference in the relative risk of venous thrombosis (OR, 4.0; 95% CI, 1.9–8.3) favoring the use of transdermal preparations. The presence of thrombophilia, particularly factor V Leiden, further amplifies the risk of venous thrombosis in women using HRT (OR, 13.16; 95% CI, 4.28–40.47). The presence of other risk factors, such as increasing age and being overweight, were all shown to be associated with a further increase in the risk of venous thrombosis.ConclusionsRecent studies have confirmed that current users of HRT are at increased risk of venous thrombosis. The increase in risk has been shown to vary according to duration of use, with the risk being greatest during the first year of use. Moreover, the increased risk varies according to the type of preparation and presence of additional risk factors such as increasing age, obesity, cancer, and recent surgery. Few studies have examined the relationship between thrombophilia, HRT and venous thrombosis; thus, more research is required in this area before accurate estimates of the risk can be made.     

Prevention of Deep Vein Thrombosis by Intermittent Pneumatic Compression of Calf

A consecutive, randomly allocated, controlled clinical trial of the prophylactic effect of intermittent pneumatic compression of the calf on the incidence of postoperative deep vein thrombosis showed that in patients without malignant disease there was a highly significant reduction in the incidence of thrombosis. In patients with malignant disease the incidence of thrombosis was higher than in those without, and there was no reduction in incidence by the application of intermittent compression. In the absence of malignant disease, severity of operation and the age of the patient were the most significant aetiological factors. We found no relation between the incidence of deep venous thrombosis and obesity, length of preoperative stay, location of hospital, or duration of anaesthesia. We suggest that intermittent pneumatic compression as used in this trial is a safe, effective, and extremely practical method of preventing postoperative deep vein thrombosis in patients not suffering from malignant disease.     

Deep venous thrombosis and pulmonary embolus after face lift: a study of incidence and prophylaxis

Deep venous thrombosis and pulmonary embolus are known risks of surgery. However, the incidence of these conditions in face lift is unknown. In this study, the incidence of deep venous thrombosis/pulmonary embolus after face lift is studied and factors associated with thromboembolic complications are evaluated. One-third of the active members of the American Society for Aesthetic Plastic Surgery were randomly selected. Participating surgeons completed a one-page survey providing information on face-lift procedures during a 12-month study period. A response rate of 80 percent was achieved, with 273 of the 342 surgeons responding to the survey. A total of 9937 face-lift procedures were reported in the 1-year study period. There were 35 patients with deep venous thrombosis (0.35 percent), 14 patients with pulmonary embolus (0.14 percent), and 1 patient death in the series. Although 43.5 percent of patients underwent face lift under general anesthesia, 83.7 percent of deep venous thrombosis/pulmonary embolus events occurred with general anesthesia. For prophylaxis for deep venous thrombosis/pulmonary embolus, 19.7 percent of the surgeons used intermittent compression devices, 19.6 percent used thromboembolic disease hose or Ace wraps, and 60.7 percent used no prophylaxis. Of patients developing deep venous thrombosis/pulmonary embolus, 4.1 percent were treated prophylactically with intermittent compression devices, 36.7 percent with thromboembolic disease hose/Ace wraps, and 59.2 percent with no prophylaxis. It was found that deep venous thrombosis/pulmonary embolus after face lift is a measurable complication experienced by one of nine surgeons surveyed. Deep venous thrombosis/pulmonary embolus is more likely to occur when the procedure is performed under general anesthesia. The majority of plastic surgeons surveyed used no prophylaxis for deep venous thrombosis when performing face-lift procedures. Intermittent compression devices were associated with significantly fewer thromboembolic complications, whereas Ace wrap/thromboembolic disease hose afforded no protection against deep venous thrombosis/pulmonary embolus when used alone. In conclusion, aesthetic surgeons should consider adopting intermittent compression devices when performing face lift under general anesthesia.     

The first case of septicemia due to nontoxigenic Corynebacterium diphtheriae in Poland: case report

Background

CMV-induced vasculopathy and thrombosis have been reported, but they are rare conditions usually encountered in immunocompromised patients. However more and more complications of CMV infections are recognized in immunocompetent patients.

Case presentation

We present a case report of a previously healthy adult with cytomegalovirus infection that was complicated by tibiopopliteal deep venous thrombosis and in whom Factor V Leiden heterozygous mutation was found.

Conclusion

This new case report emphasizes the involvement of cytomegalovirus in induction of vascular thrombosis in patients with predisposing risk factors for thrombosis. It is necessary to screen for CMV infection in patients with spontaneous thrombosis and an history of fever.     

Is the postphlebitic leg always postphlebitic? Relation between phlebographic appearances of deep-vein thrombosis and late sequelae.

One hundred and thirty legs of 67 patients were examined 5-10 years after the patient had suffered a phlebographically proved deep-vein thrombosis. Forty-seven of the limbs were normal at the time of the phlebogram, 83 contained thrombus. There was little correlation between the phlebographic severity of the thrombus and the late symptoms and signs: 32% of the legs with no thrombosis had symptoms, while 33% of the legs which had suffered severe thrombosis had no symptoms. Postphlebitic symptoms were more common in legs with aging thrombus at the time of phlebography, but upper limit of the thrombus, the age of the patient, and preexisting symptoms did not affect the incidence of late sequelae. The development of a "postphlebitic leg" does not depend solely on the extent of the initial thrombosis and can apparently develop in the absence of thrombosis.     

The effect of established infection on microvascular surgery

The success of microvascular anastomoses in the presence of staphylococcal infection was studied using rat femoral arteries. There was a spontaneous thrombosis rate of 19 percent in normal vessels that traversed the area of infection. Vessels with an anastomosis outside the area of infection had a similar thrombosis rate, but if the anastomotic site was within the infected area itself, the thrombosis rate increased to 75 percent. Inflammatory changes with subsequent fibrosis in the media and adventitia appeared responsible for the thrombosis. The intima was unaffected by the presence of infection. This study suggests that when a microvascular anastomosis is necessary in the presence of infection, the anastomosis should be placed outside the area of infection with a pedicle to traverse the infected area.