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Homocysteine and venous thrombosis: outline of a vitamin intervention trial.

In the past years several case-control studies established the association of an elevated plasma homocysteine concentration and the risk of venous thromboembolism. It is still unclear if elevated homocysteine concentrations can cause venous thrombosis. The VITRO (VItamins and ThROmbosis) trial is the first multicenter, randomized, double-blind and placebo-controlled study to evaluate the effect of homocysteine-lowering therapy by means of 5 mg folic acid, 0.4 mg vitamin B12 and 50 mg vitamin B6. The study is a secondary prevention trial in 600 patients who suffered from a first episode of idiopathic deep vein thrombosis (DVT) or pulmonary embolism (PE), or both. There will be 300 hyperhomocysteinemic and 300 normohomocysteinemic patients included, all with an objectivated venous thrombosis. The end point is recurrence of venous thrombosis.

Adult↗

[Etiology and therapy of the internal jugular vein thrombosis].

BACKGROUND: Thromboses of the upper limp and neck are rare in comparison with those of the lower extremities. Internal jugular vein thrombosis (IJVT) is a serious event with a potentially fatal outcome. Complications include pulmonary embolism, sepsis with septic emboli to different organs and tissues as well as intracranial propagation of the thrombus with cerebral edema. As any thrombosis, IJVT is precipitated by Virchow's triad: endothelial damage, alteration of blood flow and hypercoagulability. The history and examination in patients with an IJVT may be vague and misleading. Patients may present with a painful swelling of the neck but they may also be absolutely asymptomatic. Imaging procedures frequently used to diagnose an IJVT include sonography with color-coded duplex sonography, computed tomography, magnetic resonance imaging as well as magnetic resonance venography. Up to date, there is no standardized treatment regimen for patients with an IJVT. PATIENTS AND METHODS: This retrospective study includes all ten patients with an IJVT who were seen at our department between January 2000 and January 2004. There were six female and four male patients. The average age was 49.7 years, ranging from 28 to 79 years. RESULTS: In five cases, the thrombosis was associated with a malignant tumor. In four patients, it was caused by a deep neck space infection and in one case the IJVT was due to cervical, intravenous drug abuse. Two patients were found to be pregnant (one tumor patient and one patient with a deep neck space infection). In all cases, a ten day treatment regimen with intravenous antibiotics and anticoagulant therapy was initiated. Oral or subcutaneous anticoagulation was continued for six weeks to six months. No complications were seen in any patient. In three patients a revascularization of the affected vessel could be demonstrated with color-coded duplex sonography six months after the initial presentation. CONCLUSIONS: Thrombosis of the IJV is probably underdiagnosed. Since the clinical presentation may be vague or misleading, a high degree of suspicion is required to make the diagnosis. The potential complications such as pulmonary embolism or intracranial propagation of the thrombus may be fatal. Whenever the thrombosis is not caused by an inflammatory process, a malignant tumor should be excluded. We recommend a therapy with intravenous antibiotics as well as a systemic anticoagulation. Ligation or resection of the internal jugular vein is reserved for patients who develop complications despite adequate medical therapy.

Administration, Oral↗

[Prevention of deep vein thrombosis in total knee replacement--current status of therapy in orthopedie and trauma departments in Germany].

INTRODUCTION: Symptomatic deep vein thrombosis is a serious complication after total knee arthroplasty, with a risk of about 4-5% despite prevention with herparin. Aim of the current study was to find out about the actual status of thrombosis prophylaxis in Germany after total knee replacement. MATERIAL AND METHODS: In a countrywide survey 470 German trauma and orthopaedic surgery departments were asked about their prophylactic procedures addressing deep vein thrombosis after total knee replacement. RESULTS: 98% perform prevention of thrombosis with low-molecular-weight heparin, 2% use unfractioned heparin. Low-molecular-weight heparin is applicated in standard doses in 48% and in 44% according to patient's weight. In 82% the prophylaxis is begun the night before surgery. The therapy is carried out for 4.7 weeks in mean. 96% use graduated compressions stocking as additional therapeutic option. CONCLUSION: Our survey shows that most of the surgeons perform prevention of deep vein thrombosis according to the official guidelines.

Arthroplasty, Replacement, Hip↗

[Thrombosis of the inferior vena cava and the iliac and femoral veins in a 24-year old man].

HISTORY AND ADMISSION FINDINGS: A 24-year-old patient presented with nonspecific epigastric pain, general feebleness and weakness of both legs. The cardiopulmonary investigations were unremarkable. The abdomen was soft, without muscular resistance or local pressure tenderness. Both legs were moderately swollen without other findings. INVESTIGATIONS: The laboratory tests showed an elevated D-dimer and fibrinogen, as well as a heterozygous factor V Leiden mutation. Both duplex ultrasonography and computed tomography revealed thrombosis of the distal inferior vena cava (IVC) and both iliac and femoral veins. A short segment of the IVC between the left renal and intrahepatic veins was a-genetic. DIAGNOSIS, TREATMENT AND COURSE: Anticoagulation treatment with phenprocoumon was started for the deep vein thrombosis. At the one-year follow-up no thrombosis of the vena cava and the iliac and femoral veins was detected. CONCLUSION: Thrombosis of the IVC in combination with a pelvic vein thrombosis is a rare condition in young patients. If this venous abnormality is found, thrombophilia should be considered in the differential diagnosis. Anticoagulation is the treatment of choice.

Adult↗

Management of venous thrombosis and pulmonary embolism after gynecological surgery.

We experienced 23 cases of venous thrombosis after gynecological surgery for the past 12 years at Tokyo Women's Medical University Hospital, representing 0.345 % of all patients. Eighteen of the 23 cases had deep venous thrombosis (DVT) including five cases followed by pulmonary embolism (PE), and five cases had PE without any symptoms of DVT. The main risk factors for thrombosis in these 23 patients were (1) obesity, DM, hyperlipidemia; (2) huge abdominal tumor, severe adhesion; and (3) hemoconcentration, post-treatment of severe anemia. The onset of PE varied from 1 to 3 postoperative days, when the patients started to walk. Five cases had dyspnea, chest pain, and decreased PaO2 levels without leg pain, while five cases showed only calf pain and tenderness with decreased PaO2 levels. PE was confirmed by immediate diagnostic images such as RI venography with ventilation and perfusion lung scan, pulmonary arterial CT, or pulmonary arteriography. Two patients died and eight patients recovered. The best way of managing venous thrombosis might be as follows: (1) identify the risk factors of thrombosis before surgery; (2) perform prophylactic leg exercises in bed and/or active anticoagulant therapy depending on the degree of risk factors; (3) rapid diagnosis with the images; and (4) proper treatment.

Adult↗

Neonatal thrombosis with anticardiolipin antibody in baby and mother.

The anticardiolipin antibody is associated with increased risk of thrombosis, which is manifested with various clinical presentations, including vascular thrombosis, recurrent fetal wastage, and neurologic defects. We report a case of neonatal thrombosis occurring in the renal vein and inferior vena cava associated with moderate positive anticardiolipin antibody titer in the baby while the maternal serum showed even stronger anticardiolipin antibody of immunoglobulin G class. Subsequent follow-up over the 4 months postpartum period showed a disappearance of the antibody in the baby, whereas the mother's antibody persisted. This case illustrates the fact that the maternal anticardiolipin antibody can be transferred to the fetus and may be a risk factor for thrombosis in the neonates. Anticardiolipin antibody syndrome should be considered in the differential diagnosis of neonatal thrombosis.

Adult↗

Cerebral venous sinus thrombosis in children with acute lymphoblastic leukemia carrying the MTHFR TT677 genotype and further prothrombotic risk factors.

BACKGROUND: The present study was designed to prospectively evaluate the role of prothrombotic risk factors in leukemic children treated according to the ALL-BFM 90/95 study protocols with respect to the onset of cerebral venous sinus thrombosis. PATIENTS: 317 consecutive leukemic children aged 6 months to 18 years were enrolled in this study. 288 of the 317 patients were available for thrombosis-free survival analysis. RESULTS: In 17 (5.9%) of these 288 patients cerebral venous sinus thrombosis occurred. The overall event-free survival of thrombosis in the central nervous system in patients with at least one prothrombotic defect (n = 12) was significantly reduced compared with patients without a prothrombotic defect (p < 0.0001). 15 patients showed acute clinical symptoms at onset of cerebral venous sinus thrombosis, two were asymptomatic. Three of the 17 patients affected (17.6%) died directly associated with the thrombotic event during induction therapy, the remaining 14 patients did not show prolonged clinical symptoms. CONCLUSIONS: Prothrombotic risk factors should be included in a screening program in ALL children treated according to the BFM study protocols. Further prospective studies are recommended to establish adequate prophylactic anticoagulant treatment during ALL (BFM) polychemotherapy.

Adolescent↗

Cerebral sinovenous thrombosis in children.

BACKGROUND: Cerebral sinovenous thrombosis in children is a serious disorder, and information is needed about its prevention and treatment. METHODS: The Canadian Pediatric Ischemic Stroke Registry was initiated in 1992 at the 16 pediatric tertiary care centers in Canada. Children (newborn to 18 years of age) with symptoms and radiographic confirmation of sinovenous thrombosis were included. RESULTS: During the first six years of the registry, 160 consecutive children with sinovenous thrombosis were enrolled, and the incidence of the disorder was 0.67 cases per 100,000 children per year. Neonates were most commonly affected. Fifty-eight percent of the children had seizures, 76 percent had diffuse neurologic signs, and 42 percent had focal neurologic signs. Risk factors included head and neck disorders (in 29 percent), acute systemic illnesses (in 54 percent), chronic systemic diseases (in 36 percent), and prothrombotic states (in 41 percent). Venous infarcts occurred in 41 percent of the children. Fifty-three percent of the children received antithrombotic agents. Neurologic deficits were present in 38 percent of the children, and 8 percent died; half the deaths were due to sinovenous thrombosis. Predictors of adverse neurologic outcomes were seizures at presentation and venous infarcts. CONCLUSIONS: Sinovenous thrombosis in children affects primarily neonates and results in neurologic impairment or death in approximately half the cases. The occurrence of venous infarcts or seizures portends a poor outcome.

Adolescent↗

Use of the low-molecular-weight heparin reviparin to prevent deep-vein thrombosis after leg injury requiring immobilization.

BACKGROUND: Deep-vein thrombosis is a well-recognized complication after trauma to the legs and subsequent immobilization, but there are no generally accepted approaches to preventing this complication. METHODS: We performed a prospective, double-blind, placebo-controlled trial to evaluate the efficacy and safety of subcutaneous reviparin (1750 anti-Xa units given once daily) in 440 patients who required immobilization in a plaster cast or brace for at least five weeks after a leg fracture or rupture of the Achilles tendon. The study drug was given throughout the period of immobilization. Venography of the injured leg was performed within one week after removal of the plaster cast or brace, or earlier if there were symptoms suggesting deep-vein thrombosis. RESULTS: Data on efficacy and end points were available for 371 patients. Deep-vein thrombosis was diagnosed in 17 of the 183 patients randomly assigned to receive reviparin (9 percent) and in 35 of the 188 patients randomly assigned to receive placebo (19 percent) (odds ratio, 0.45; 95 percent confidence interval, 0.24 to 0.82). Most of the thromboses were distal (14 in the reviparin group and 25 in the placebo group). There were two cases of pulmonary embolism, both in patients in the placebo group who also had proximal deep-vein thrombosis. There were no differences between the two groups with respect to bleeding or other adverse events. CONCLUSIONS: Deep-vein thrombosis is common in persons with leg injury requiring prolonged immobilization. Reviparin given once daily appears to be effective and safe in reducing the risk of this complication.

Achilles Tendon↗

Catheter-related thrombosis in children with cancer.

OBJECTIVE: The prevalence of asymptomatic catheter-related thrombosis of the upper venous system in children with cancer has not been determined. We evaluated patients with cancer and implantable central venous catheters (ports) for this complication. STUDY DESIGN: Children with cancer undergoing port removal were eligible for this study. Vessel patency was evaluated by contrast venography. We examined each child for physical stigmata of thrombosis and retrospectively assessed catheter-related mechanical difficulties and infections. RESULTS: Thirty-one ports had been placed in 24 children (aged 20 months to 18 years; median age, 9 years) with diagnoses of leukemia/lymphoma (n = 10), solid tumor (n = 12), and histiocytosis (n = 2). Venography showed abnormalities in 12 of the 24 patients. Physical examination revealed dilated superficial veins on the chest in 3 patients. Venograms showed abnormalities in all 3 children with prominent superficial thoracic veins. Nine of the 21 other patients had clinically occult central venous occlusion. CONCLUSION: Fifty percent (95% CI, 30% to 70%) of children who had implantable ports removed during or after treatment of cancer exhibited deep venous thrombosis at the site of catheter placement. Future studies should determine the contribution of inherited and other acquired risk factors for thrombosis and assess measures to prevent and/or treat catheter-related thrombosis in this population.

Adolescent↗

Ocular expression of vascular cell adhesion molecule (VCAM-1) in 2-butoxyethanol-induced hemolysis and thrombosis in female rats.

We demonstrated previously that exposure of rats to 2-butoxyethanol (BE) was associated with morphological changes in red blood cells, hemolytic anemia, and disseminated thrombosis and infarction in different organs including the eyes. In order to elucidate the mechanism of thrombosis formation, we examined in this study the histology and immunohistochemical expression of vascular cell adhesion molecule-1 (VCAM-1), endothelial intercellular adhesion molecule-1 (ICAM-1), and P-selectin in the eyes of the female F344 rat exposed to 2, 3, or 4 daily doses of BE/250 mg/kg body weight. In this BE hemolysis and thrombosis model, positive VCAM-1 expression occurred only in eyes of rats exposed to 3 and 4 doses and was localized in the iris (epithelium lining the posterior surface, anterior mesenchymal epithelium), ciliary processes (lining epithelium, stromal cells), and retina (hypertrophic retinal pigment epithelium). Only weak immunolabeling was seen in eyes exposed to 2 doses. The appearance of VCAM-1 immunostaining correlated with the development of thrombosis located in the same structures. No change in ICAM-1 or P-selectin expression was seen. This immunolabeling distribution suggests that VCAM-1 functions in the pathogenesis of BE-related thrombosis by promoting adhesion of erythrocytes to the endothelium.

Animals↗

Venous thrombosis associated with pernicious anaemia. A report of two cases and review.

Since homocystinuria, an inborn metabolism error is complicated by venous thrombosis in about half of the patients, hyperhomocysteinemia has been suspected of favouring thrombosis. Several case-control studies and even meta-analysis have confirmed a link between venous thrombosis and mild hyperhomocysteinemia. Nevertheless, the proper role of homocysteine remains debated. Hyperhomocysteinemia is induced by vitamin B9 or B12 deficiencies in a vast majority of cases. The authors report on two patients with venous thrombosis revealing pernicious anemia and review nine similar cases found in the world literature. The literature concerning the relationships between homocysteine and venous thrombosis is briefly reviewed.

Aged↗

Spontaneous internal jugular vein thrombosis: primary manifestation of a colorectal adenocarcinoma in a very old woman.

We report the history of a very old woman with a spontaneous internal jugular vein thrombosis as the presenting feature of an occult adenocarcinoma of the caecum. Spontaneous internal jugular vein thrombosis is an unusual form of venous thrombosis. Doppler ultrasound and Computed Tomography or Magnetic Resonance Imaging should confirm signs and symptoms suggesting thrombosis. Immediate anticoagulation with heparin followed by oral anticoagulation is mandatory to reduce associated mortality and morbidity. If no risk factors for internal jugular vein thrombosis are present, a work-up for hypercoagulable states and a careful search for distant malignancy should been obtained. If screening shows no obvious malignancy, further follow-up is necessary.

Adenocarcinoma↗

Homocysteine and vascular access thrombosis in hemodialysis patients.

BACKGROUND: Vascular access remains the Achilles' heel of successful hemodialysis, and thrombosis is the leading cause of vascular access failure. Hyperhomocystinemia is common in hemodialysis patients and is associated with venous and arterial thrombosis in patients without end-stage renal disease. SUBJECTS AND METHODS: In the study, 65 hemodialysis patients with native arteriovenous fistula were included. Two groups of patients were defined: group A including 45 patients with their vascular access either never or only once thrombosed, and group B including 20 patients with two or more thromboses of their vascular access. We determined serum concentrations of total homocysteine (immunoassay, Abbott) in our patients. RESULTS: In 63 (96.9%) patients, hyperhomocystinemia was presented. There was no statistically significant difference between group A and B regarding age, gender and duration of hemodialysis treatment. Total homocysteine concentrations were higher in group A (42.1 +/- 18.6 micromol/l) than in group B (36.1 +/- 18.1 micromol/l) patients but the difference was small and not statistically significant. CONCLUSION: We found no significant differences in total homocysteine concentrations between group A (thrombosis non-prone) and group B (thrombosis prone) patients. Our results suggest that thrombosis of native arteriovenous fistulas may not be caused by hyperhomocystinemia in these patients.

Adult↗

Homocysteine and vascular access thrombosis in a cohort of end-stage renal disease patients.

BACKGROUND: Maintaining successful hemodialysis services is dependent upon an access to circulation that is reliable and stable. Complications of vascular access such as dysfunction, thrombosis, or infection are major causes of hospitalization with thrombosis being the most common reoccurring problem. Initial prospective evidence supports an independent association between total homocysteine (tHcy) levels and access thrombosis. The purpose of this study was to determine if significant associations exist between tHcy, age, gender, and vascular access thrombosis in patients with end-stage renal disease (ESRD). SUBJECTS AND METHODS: One hundred eighty-five (N=185) patients undergoing dialysis were selected as subjects. The retrospective sample was divided into a one or less vascular access thrombosis (VAT) (VAT) group (n= 133) and more than one (VAT II) VAT group (n= 52). The data was collected during a 16-month period (January 2000 to April 2002). Additional subgroup analyses included gender and age. RESULTS: The Mann-Whitney U nonparametric t-Test for variance between groups revealed no significant difference in tHcy values between VAT groups (U=1841.50, p=0.284). A two-sample t-Test for variance between tHcy and age revealed no significant differences (F-ratio = 0.832, p = 0.32). A chi-square analysis revealed no significant differences in gender and VAT groups (chi2=0.246, p=0.62). A Kolmogorov-Smirnov test for normality was calculated for tHcy with a p-value of 0.859 revealing insufficient evidence that the distribution is not normal. Spearman Rank Correlations were calculated, revealing low to moderate associations among variables. CONCLUSIONS: While some studies have demonstrated a relationship between tHcy and VAT, this study found that chronically high homocysteine levels in patients with ESRD were not associated with incidence of VAT. There were no significant differences in the number of VATs across additional variables of age and gender.

Age Distribution↗

AIDS and thrombosis: retrospective study of 131 HIV-infected patients.

The recent literature contains reports of thrombotic episodes occurring in patients with human immunodeficiency virus (HIV) infection and various abnormalities predisposing to a hypercoagulable state have also been reported in such patients. To study the incidence of thrombosis in patients infected with HIV, and to assess the correlation of thrombosis with the degree of immunosuppression as well as the association with active illnesses and neoplasms, we reviewed the charts of 131 patients, which include all the patients with the diagnosis of HIV admitted or seen in the clinic between January 1, 1993, and January 1, 1998. The diagnosis of thrombosis was based on documented reports of venous plethysmography or venography for deep venous thrombosis and ventilation-perfusion scan or pulmonary angiography for pulmonary embolus. Risk factors for thrombotic disease were evaluated including general risk factors such as family history, ambulatory status, medications, and data were also collected regarding CD4 cell counts and the presence of concurrent or remote opportunistic infections, acquired immune deficiency syndrome (AIDS)-related malignancy or other AIDS-related diseases at the time of diagnosis of the thrombotic event. We also reviewed the medical literature via MEDLINE and found 45 cases of patients with HIV who developed thromboembolic complications. We found thrombotic complications in 9 of 37 patients with a CD4 count less than 200 cells/mm3 and in 1 of the remaining 94 patients with a CD4 count more than 200 cells/mm3. The difference was significant, with p = 0.00004, and the estimated odds of an event given CD4 cell counts less than 200/mm3 is 29.89 (95% confidence interval). Three patients had abnormalities of anticoagulation proteins. There was a history of opportunistic infections in 5 patients and malignancy in 3 patients. Two patients with autoimmune hemolytic anemia (AIHA) secondary to HIV-infection developed PE upon transfusion of packed red blood cells. The results of this study suggests that AIDS appears to predispose to thrombosis. It also revealed a significant correlation between thrombotic disease and CD4 counts (<200/mm3) as well as the presence of opportunistic infections, AIDS-related neoplasms, or autoimmune disorders associated with HIV such as AIHA. Therefore, clinicians caring for these patients should be aware of thromboembolic disease as a possible complication of AIDS. Further studies to elucidate the mechanisms underlying this abnormal hemostatic profile, the epidemiology, and to answer several questions such as should patients with risk factors for HIV infection who develop thromboembolic complications be further evaluated including tests for HIV are warranted.

AIDS-Related Opportunistic Infections↗

Recurrent miscarriage and long-term thrombosis risk: a case-control study.

BACKGROUND: Recurrent miscarriage has been associated with antiphospholipid syndrome (APS) and other prothombotic conditions. We tested the hypothesis that women diagnosed as having APS as an aetiological factor for their miscarriages were at higher risk of thrombosis than those with idiopathic recurrent miscarriage. METHODS: A retrospective case-control study was performed using validated questionnaires. A total of 141 women with recurrent miscarriage and APS alone were matched with 141 women with idiopathic recurrent miscarriage for age, number and type of pregnancy loss and number of years of follow-up. A subgroup of eight women included those who initially presented with recurrent miscarriage, thrombosis and APS. RESULTS: The mean length of follow-up was 7.3 years and response rate 74%. The incidence of thrombosis was similar in the recurrent miscarriage and APS women (6/1000 women-years) and in the idiopathic recurrent miscarriage women (2/1000 women-years) (P = 0.18). All eight women who presented with recurrent miscarriage, APS and thrombosis reported further thrombotic events. CONCLUSIONS: Both idiopathic and APS-associated recurrent miscarriage were associated with a similar long-term risk of thrombosis.

Abortion, Habitual↗

Renal allograft thrombosis: can thrombophilia explain the inexplicable?

Renal allograft thrombosis remains a preventable cause of early allograft thrombosis. It should not be considered simply an unpredictable and poorly understood consequence of surgery. Extrapolated data from the general population and early data from renal patients supports the concept that the interplay of non-inherited hypercoagulability of renal disease with inherited thrombophilia, and the altered environmental milieu of transplantation predisposes to thrombosis (summarized in Figure 2). We should not accept the inevitability of a constant attrition of grafts to thrombosis and need to continue to identify risk factors and confirm appropriate screening and interventions for its prevention, almost certainly requiring collaborative multicentre trials. In the future, just as we now expand the specificity of HLA gene typing with molecular biology, genotyping for recognized thrombophilia genes in patients at risk will expand our ability to recognize and prevent thrombosis with targeted interventions drawn from the increasing array of anticoagulants now available. The contribution of thrombophilia to non-immune mechanisms of chronic allograft loss is also a potentially important but neglected area of research.

Humans↗