Prevalence of the factor V Leiden mutation in hepatic and portal vein thrombosis.

BACKGROUND: The factor V Leiden (FVL) mutation has been shown to be the most frequent cause of hereditary thrombophilia. The prevalence of the mutation in patients with Budd-Chiari syndrome (BCS) and portal vein thrombosis (PVT) has not been fully elucidated. AIMS: To investigate the association between the FVL mutation and BCS and PVT. PATIENTS: Thirty patients with BCS, 32 patients with PVT, and a control group of 54 patients with liver disorders and no history of thrombosis. METHODS: The factor V gene was analysed for the presence of the FVL mutation by a polymerase chain reaction (PCR) technique. The presence of the mutation was confirmed by DNA sequencing. RESULTS: Seven (23%) patients with BCS, one (3%) patient with PVT, and three (6%) patients in the control group were identified as having the FVL mutation. There of the BCS patients had coexisting hypercoagulable states. The prevalence of the FVL mutation was significantly higher in patients with BCS compared with patients with PVT and controls (p < 0.04). The FVL mutation was the second most common aetiology associated with BCS. CONCLUSION: The FVL mutation is an important factor in the pathogenesis of BCS and screening for the disorder must be included in the investigation of patients presenting with this condition. In contrast, the FVL mutation is not a major predisposing factor in the pathogenesis of PVT.     

因子V Leiden突变在布加综合征与门静脉血栓形成中的意义

布加综合征与门静脉血栓是2种罕见的肝脏血管病,可伴发肝功能衰竭及门静脉高压症等严重并发症。研究证据表明因子V Leiden(FVL)突变是西方布加综合征与门静脉血栓患者的重要危险因素,但在中国布加综合征患者中比较罕见。着重回顾FVL突变在布加综合征与门静脉血栓形成中的意义,提出尚须前瞻性研究进一步评估FVL突变在中国门静脉血栓患者中的患病率,以判断FVL突变筛查的必要性。     

Factor V Leiden is not commonly associated with idiopathic portal vein thrombosis in southern India.

BACKGROUND: Factor V Leiden has been reported in 2%-30% of patients with portal vein thrombosis. This wide variation makes it difficult to assess the importance of factor V Leiden as a predisposing factor. METHODS: Factor V Leiden was determined by restriction fragment length polymorphism in 112 patients with portal vein thrombosis, 104 with deep vein thrombosis and 98 control subjects. RESULTS: Only 3/112 (3%) patients with portal vein thrombosis had factor V Leiden, compared to 1/98 (1%) controls and 16/104 (15%) with deep vein thrombosis; of these, 3, 1 and 15, respectively, were heterozygous for this mutation. CONCLUSION: Factor V Leiden contributes little, if at all, to the development of portal vein thrombosis in southern India.     

Mesenteric and portal vein thrombosis associated with hyperhomocysteinemia and heterozygosity for factor V Leiden mutation

TO THE EDITOR A 79-year-old man was hospitalized because of worsening upper abdominal pain which started two days before admission and was continuously present. His personal and family historywas uneventful, he did not smoke and denied toxic habits or using any medications, including over the-counter medications, herbal remedies or any vitamin supplements.     

Budd-Chiari syndrome, portal vein and mesenteric vein thrombosis in a patient homozygous for factor V Leiden mutation treated by TIPS and thrombolysis

We present the first case of Budd-Chiari syndrome in association with portal and mesenteric vein thrombosis in a patient homozygous for the factor V Leiden mutation. She was treated by transjugular intrahepatic portosystemic stent (TIPS) placement followed by local thrombolytic therapy. Venous outflow from the liver was established and the thrombi in the portal and mesenteric veins were lysed completely. This therapeutic approach may be used for such patients with this severe thrombotic event, who generally have a poor prognosis.     

Spontaneous venous thrombosis in a young patient with combined factor V Leiden and lupus anticoagulant.

We describe a case of a 28-year-old man who developed an extensive spontaneous deep venous thrombosis. Testing revealed heterozygotic factor V Leiden mutation, and the presence of both lupus anticoagulant (LA) and elevated IgM anticardiolipin antibody (ACA). Several family members were found to be heterozygous for factor V Leiden. A paternal aunt had the factor V Leiden mutation, an elevated plasma homocysteine and a borderline increased IgG ACA level. No other family member had a history of a venous thrombotic event. This case illustrates that evaluation of young patients who present with venous thrombosis should be performed for both hereditary and acquired thrombophilic defects. The family studies suggest that the presence of a lupus anticoagulant may be more clinically significant than elevated ACA in risk assessment. Although screening family members when the proband carries factor V Leiden is controversial, psychological reassurance of those who test negative and simple advice on occupations or social habits (e.g., smoking) for those who test positive may be important benefits.     

The factor V Leiden mutation in children with cancer and thrombosis

Thromboembolic phenomena, frequently observed in children with cancer who are undergoing chemotherapy, can cause significant morbidity and, less frequently, mortality. Many contributory factors have been identified. Whether the recently identified and most common coagulation defect predisposing to thrombosis, factor V Leiden, is associated with thrombosis in this setting, has not been explored. The current study was undertaken to determine the prevalence of the factor V Leiden mutation in children with cancer who developed thromboembolic phenomena as compared to those with cancer who did not. Genomic DNA was amplified using the polymerase chain reaction (PCR), followed by digestion of the amplification product with the restriction enzyme Mnl I. The digested PCR products were then size-fractionated to classify samples as heterozygous, homozygous or normal for the factor V Leiden mutation. 67 children with cancer were evaluated for the factor V Leiden mutation. One of 32 children with cancer and thrombosis, and none of 35 who had not experienced thrombotic problems, was found heterozygous for this mutation. We conclude that the factor V Leiden mutation does not play a significant role in the overall incidence of thromboses that occur in children with cancer.     

Factor V Leiden: a disorder of factor V anticoagulant function

PURPOSE OF REVIEW: Activated protein C (APC) resistance, which is often associated with the factor V R506Q (FV Leiden) mutation, is a common risk factor for venous thrombosis. Study of the mechanism of APC resistance has revealed that coagulation FV stimulates the APC-catalysed inactivation of FVIIIa, and that this anticoagulant function of FV is impaired in FV Leiden. The present review covers the discovery, the physiological significance and the structural requirements of the APC-cofactor activity of FV. RECENT FINDINGS: Recent in vitro and in vivo experiments indicate that the anticoagulant activity of FV is physiologically relevant and that FV plays a major role in the maintenance of the haemostatic balance. Quantitative and functional defects of the APC-cofactor activity of FV lead to increased thrombin generation and are associated with a prothrombotic state. Although the structural requirements for the expression of the APC-cofactor activity of FV are now beginning to be unravelled, the underlying molecular mechanism remains elusive. SUMMARY: The APC-cofactor activity of FV and its impairment in FV Leiden can explain the different thrombosis risks associated with heterozygosity, homozygosity and pseudo-homozygosity for FV Leiden. Elucidation of the molecular mechanism of the anticoagulant function of factor V may provide novel targets for the design of antithrombotic drugs.     

Spontaneous thrombosis in mice carrying the factor V Leiden mutation

A polymorphism in coagulation factor V, factor V Leiden (FVL), is the major known genetic risk factor for thrombosis in humans. Approximately 10% of mutation carriers experience clinically significant thrombosis in their lifetime. In a small subset of patients, thrombosis is associated with coinheritance of other prothrombotic gene mutations. However, the potential contribution of additional genetic risk factors in the majority of patients remains unknown. To gain insight into the molecular basis for the variable expressivity of FVL, mice were generated carrying the homologous mutation (R504Q [single-letter amino acid codes]) inserted into the endogenous murine Fv gene. Adult heterozygous (FvQ/+) and homozygous (FvQ/Q) mice are viable and fertile and exhibit normal survival. Compared with wild-type mice, adult FvQ/Q mice demonstrate a marked increase in spontaneous tissue fibrin deposition. No differences in fetal development or survival are observed among FvQ/Q, FvQ/+ or control littermates on the C57BL/6J genetic background. In contrast, on a mixed 129Sv-C57BL/6J genetic background, FvQ/Q mice develop disseminated intravascular thrombosis in the perinatal period, resulting in significant mortality shortly after birth. These results may explain the high degree of conservation of the R504/R506 activated protein C cleavage site within FV among mammalian species and suggest an important contribution of other genetic factors to the thrombosis associated with FVL in humans. (Blood. 2000;96:4222-4226)     

Factor V Leiden mutation, prothrombin gene mutation, and deficiencies in coagulation inhibitors associated with Budd-Chiari syndrome and portal vein thrombosis: results of a case-control study

In a collaborative multicenter case-control study, we investigated the effect of factor V Leiden mutation, prothrombin gene mutation, and inherited deficiencies of protein C, protein S, and antithrombin on the risk of Budd-Chiari syndrome (BCS) and portal vein thrombosis (PVT). We compared 43 BCS patients and 92 PVT patients with 474 population-based controls. The relative risk of BCS was 11.3 (95% CI 4.8-26.5) for individuals with factor V Leiden mutation, 2.1(95% CI 0.4-9.6) for those with prothrombin gene mutation, and 6.8 (95% CI 1.9-24.4) for those with protein C deficiency. The relative risk of PVT was 2.7 (95% CI 1.1-6.9) for individuals with factor V Leiden mutation, 1.4 (95% CI 0.4-5.2) for those with prothrombin gene mutation, and 4.6 (95% CI 1.5-14.1) for those with protein C deficiency. The relative risk of BCS or PVT was not increased in the presence of inherited protein S or antithrombin deficiency. Concurrence of either acquired or inherited thrombotic risk factors was observed in 26% of the BCS patients and 37% of the PVT patients. We conclude that factor V Leiden mutation and hereditary protein C deficiency appear to be important risk factors for BCS and PVT. Although the prevalence of the prothrombin gene mutation was increased, it was not found to be a significant risk factor for BCS and PVT. The coexistence of thrombogenic risk factors in many patients indicates that BCS and PVT can be the result of a combined effect of different pathogenetic mechanisms.     

Factor V Leiden and prothrombin gene G20210A mutations are uncommon in portal vein thrombosis in India.

BACKGROUND: Extra-hepatic portal vein obstruction due to portal vein thrombosis (PVT) is an important cause of portal hypertension in several regions including India. The cause of thrombosis in these patients remains unclear. We studied the frequency of mutations in genes for coagulation factors V and II (prothrombin) in 61 Indian patients with PVT and 49 healthy control subjects. METHODS: The presence of factor V Leiden mutation and of G20210A prothrombin gene mutation was determined using polymerase chain reaction followed by restriction fragment length polymorphism. Chi-squared test was used to compare patients and controls. RESULTS: Of the 61 patients (median age 11 years; 47 male) studied, 49 were children. One of 61 (1.6%) patients with PVT was heterozygous for factor V Leiden mutation and none had the G20210 prothrombin gene mutation. The frequencies of these mutations were not different from those in control subjects (2/49 and 0/46, respectively). CONCLUSION: Factor V Leiden and G20210 prothrombin gene mutations are infrequent in Indian patients with PVT. Thus, these mutations are unlikely to be responsible for PVT in the Indian population.     

Prevalence of factor V Leiden mutation and other hereditary thrombophilic factors in Egyptian children with portal vein thrombosis: results of a single-center case-control study

No identifiable cause can be found in more than half of the cases of portal vein thrombosis (PVT). Our aim was to assess the prevalence of factor V Leiden mutation and other thrombophilic factors as risk factors in the development of PVT in the pediatric age group. From March 2001 to January 2002, 40 children with PVT were enrolled in the study, in addition to 20 age-matched and sex-matched controls. Protein C, protein S, antithrombin III, and activated protein C resistance (APCR) were assayed. Molecular study of factor II and factor V mutations was carried out. Of the patients, 25 had detectable hereditary thrombophilia (62.5%), 12 had factor V Leiden mutation (30%), 11 had protein C deficiency (27.5%), 6 had factor II mutation (15%), 1 had antithrombin III deficiency (2.5%), and none had protein S deficiency. Five children had concurrence of more than one defect. Factor V Leiden mutation is the most common hereditary thrombophilia associated with PVT and the relative risk of factor V Leiden mutation, as a cause of PVT, was six times more than in controls (odds ratio=6). Concurrence of more than one hereditary thrombophilic factor was seen in 12.5% of our patients. Circumstantial risk factors (neonatal sepsis, umbilical sepsis, umbilical catheterization) were not more significantly prevalent among patients with hereditary thrombophilia than among those with no detectable abnormalities in anticoagulation.An erratum to this article can be found at     

Hepatic and portal vein thrombosis in cirrhosis: Possible role in development of parenchymal extinction and portal hypertension

Obliterative lesions in portal veins (PVs) and hepatic veins (HVs) of all sizes are known to occur in cirrhotic livers. PV lesions have generally been attributed to thrombosis, but the pathogenesis of the HV (veno-occlusive) lesions is unknown. We have studied 61 cirrhotic livers removed at transplantation to clarify the prevalence, distribution, and pathogenesis of venous lesions, as well as the association of these lesions with other morphological features and clinical morbidity. Intimal fibrosis that is highly suggestive of healed HV or PV thrombosis was found in at least 70% and 36% of livers, respectively. The distribution of HV lesions was patchy and largely confined to veins between 0.1 and 3 mm in diameter, suggesting multifocal origin in small veins. PV lesions were more uniform throughout the liver, suggesting origin in large veins with propagation to the small veins. HV lesions were associated with regions of confluent fibrosis (focal parenchymal extinction), and PV lesions were associated with regional variation in the size of cirrhotic nodules and a history of bleeding varices. These observations suggest that thrombosis of medium and large PVs and HVs is a frequent occurrence in cirrhosis, and that these events are important in causing progression of cirrhosis.     

Study of portal vein thrombosis in patients with idiopathic portal hypertension in Japan.

BACKGROUND/AIMS: The aim of this study was to elucidate the incidence and clinical manifestations of portal vein thrombosis (PVT) in patients with idiopathic portal hypertension (IPH) in Japan during long-term follow-up. PATIENTS AND METHODS: Twenty-two patients with IPH were examined for PVT by sonography during a follow-up of 12+/-6 years. Clinical manifestations and patient outcome related to PVT were studied. Seventy patients with liver cirrhosis were examined by sonography as an incidence control of thrombosis. RESULTS: Nine IPH patients had portal thrombosis (9/22, 41%), a higher incidence than in liver cirrhosis patients (7/70, 10%). Those with thrombosis showed ascites, marked hypersplenism, and low serum albumin. Four patients with thrombosis died. Patients without thrombosis showed less clinical problems after long-term follow-up. Plasma antithrombin III and protein C activity decreased in almost half of the patients. However, there were no differences in these parameters between patients with and without thrombosis. CONCLUSIONS: In Japan, IPH patients had a high incidence of portal thrombosis, a significant factor for poor prognosis. Whether the management of PVT contributes to an improvement of a clinical course of IPH or not should be clarified in further study.     

Development of portal vein thrombosis complicating idiopathic portal hypertension. A case report

A 58-yr-old woman with biopsy-proven idiopathic portal hypertension presented with ascites and pretibial pitting edema. On admission, ultrasonic Doppler flowmetry demonstrated hepatopetal flow of a markedly reduced velocity in the portal vein, hepatofugal flow in the splenic vein, and a large spontaneous splenorenal shunt. The patient spontaneously developed hepatic encephalopathy 1 mo later. Percutaneous transhepatic portography demonstrated mural thrombi at the porta hepatis after the catheter had penetrated the mural thrombi without resistance; there was also a long retention of contrast medium in the portal vein. 99mTc-Macroaggregated albumin instilled into the superior mesenteric vein was caught in the lungs, and no activity entered the liver. Measurements of ammonia and immunoreactive insulin clearly indicated that superior mesenteric venous blood was shunted through the splenic vein and the splenorenal shunt. Subsequent ultrasonic examination with Doppler flowmetry suggested further growth of the thrombi and lack of blood flow in the portal vein. Although the procedure of percutaneous transhepatic catheterization could have contributed to the growth of thrombi, it is more likely that the thrombosis in the portal vein was a sequela to idiopathic portal hypertension, and was growing at the time of catheterization. This case may be of significance in the understanding of the relationship between idiopathic portal hypertension and extrahepatic portal obstruction.     

Effectiveness of combined anticoagulant therapy for extending portal vein thrombosis in Crohn's disease

PURPOSE: Portal vein thrombosis is a rare complication of Crohn's disease, and its precise cause and appropriate treatment are not known. We describe a patient with extending portal vein thrombosis in Crohn's disease who was successfully treated with combined anticoagulant therapy. METHOD: Urokinase and tissue plasminogen activator were administered from a catheter inserted into the superior mesenteric artery, and heparin and a serine protease inhibitor also were given intravenously. RESULTS: On admission, thromboembolic occlusion was observed throughout the entire portal venous system in association with massive ascites and remarkable intestinal edema. After administration of combined anticoagulant therapy, thrombus rapidly decreased in size, and color Doppler ultrasonography showed a gradual increase in portal venous flow. The patient had no recurrence of symptoms while receiving warfarin after resolution of thrombus. CONCLUSION: This case report suggests that combined anticoagulant therapy is effective for patients with severe portal vein thrombosis in Crohn's disease and that color Doppler ultrasonography is useful for evaluation of portal venous flow.